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Introduction: Cannabis use for pain relief is commonly reported, yet laboratory studies and clinical trials suggest that cannabinoids are weak analgesics, and it is unclear whether perceived reductions in pain from before to after cannabis use relate to factors such as dose, method of administration, phytocannabinoid content, or the age or gender of the user. We determined whether inhalation of cannabis decreased self-reported pain ratings as well as whether user gender, age, time, method of administration, tetrahydrocannabinol (THC)/cannabidiol (CBD) content, or dose of cannabis contribute to changes in these ratings. We also examined whether tolerance may develop to the analgesic effects of cannabis over time. Materials and Methods: Archival data were obtained from Strainprint(®), a medical cannabis app that allows patients to track symptoms before and after using different strains and doses of cannabis. Latent change score models and multilevel models were used to analyze data from 131,582 sessions in which inhaled cannabis was used to treat “muscle pain,” “joint pain,” or “nerve pain.” Results: For all three pain symptoms, severity ratings decreased significantly after cannabis use. Women reported higher baseline and postcannabis pain severity than did men, and men reported larger decreases in pain than did women. Neither THC nor CBD content nor their interaction predicted reductions in pain ratings. However, vaping was associated with larger reductions in joint pain ratings than was smoking, and lower doses were associated with larger reductions in nerve pain ratings. Additionally, for all three pain symptoms, the dose of cannabis used to manage pain increased significantly over time. Conclusions: Inhaled cannabis reduces self-reported pain severity by ∼42–49%. However, these reductions appear to diminish across time, and patients use larger doses across time, suggesting that analgesic tolerance develops with continued use.

Use of cannabis to alleviate headache and migraine is relatively common, yet research on its effectiveness remains sparse. We sought to determine whether inhalation of cannabis decreases headache and migraine ratings as well as whether gender, type of cannabis (concentrate vs flower), delta-9-tetrahydrocannabinol, cannabidiol, or dose contribute to changes in these ratings. Finally, we explored evidence for tolerance to these effects. Archival data were obtained from Strainprint, a medical cannabis app that allows patients to track symptoms before and after using different strains and doses of cannabis. Latent change score models and multilevel models were used to analyze data from 12,293 sessions where cannabis was used to treat headache and 7,441 sessions where cannabis was used to treat migraine. There were significant reductions in headache and migraine ratings after cannabis use. Men reported larger reductions in headache than women and use of concentrates was associated with larger reductions in headache than flower. Further, there was evidence of tolerance to these effects. PERSPECTIVE: Inhaled cannabis reduces self-reported headache and migraine severity by approximately 50%. However, its effectiveness appears to diminish across time and patients appear to use larger doses across time, suggesting tolerance to these effects may develop with continued use.

Chronic pain is the most common reason reported for using medical cannabis. The goal of this research was to determine whether the two primary phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), are effective treatments for persistent inflammatory pain. In experiment 1, inflammation was induced by intraplantar injection of Complete Freund’s adjuvant (CFA). Then THC (0.0–4.0 mg/kg, i.p.) or CBD (0.0–10 mg/kg, i.p.) was administered twice daily for 3 days. On day 4, THC, CBD, or vehicle was administered, and allodynia, hyperalgesia, weight-bearing, locomotor activity, and hindpaw edema were assessed 0.5–4 hours postinjection. In experiment 2, CFA or mineral oil (no-pain control)-treated rats were given THC (2.0 mg/kg, i.p.), CBD (10 mg/kg, i.p.), or vehicle in the same manner as in experiment 1. Four hours postinjection on day 4, serum samples were taken for analysis of cytokines known to influence inflammatory pain: interleukin (IL)-1β, IL-6, IL-10, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α. THC dose-dependently reduced pain-related behaviors but did not reduce hindpaw edema, and little tolerance developed to THC’s effects. In contrast, CBD effects on inflammatory pain were minimal. THC produced little to no change in serum cytokines, whereas CBD decreased IL-1β, IL-10, and IFN-γ and increased IL-6. Few sex differences in antinociception or immune modulation were observed with either drug, but CFA-induced immune activation was significantly greater in males than females. These results suggest that THC may be more beneficial than CBD for reducing inflammatory pain in that THC maintains its efficacy with short-term treatment in both sexes and does not induce immune activation. SIGNIFICANCE STATEMENT: The pain-relieving effects of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) are examined in male and female rats with persistent inflammatory pain to determine whether individual phytocannabinoids could be a viable treatment for men and women with chronic inflammatory pain. Additionally, sex differences in the immune response to an adjuvant and to THC and CBD are characterized to provide preliminary insight into immune-related effects of cannabinoid-based therapy for pain.

Chemotherapeutic agents can cause peripheral neuropathy, a deleterious side effect of cancer treatment. Hyperbaric oxygen (HBO2) treatment has shown great potential for decreasing pain in numerous clinical pain conditions and in preclinical studies. This study was designed to test whether HBO2 might also be useful for treating chemotherapy-induced peripheral neuropathy. Male and female Sprague-Dawley rats were injected with 1 mg/kg paclitaxel or vehicle every other day for 7 days to induce allodynia, followed by either one single, or four daily 60-min exposures to HBO2 or room air. Mechanical and cold allodynia as well as locomotor behavior and body weight were assessed intermittently for several weeks. Estrous cycling was also tracked in female rats. Paclitaxel caused pronounced mechanical allodynia in both sexes that was completely reversed by either one or four treatments of HBO2. Females in all treatment groups showed greater cold acetone scores than males, and acetone scores were not reliably reduced by HBO2 treatment. Neither paclitaxel nor HBO2 treatment altered locomotor behavior or estrous cycling. We conclude that HBO2 treatment was highly effective at reducing mechanical allodynia in paclitaxel-treated rats without affecting weight gain, locomotion, or estrous cycling, suggesting that HBO2 may be effective for treating chemotherapy-induced neuropathic pain without producing significant side effects.

Studies have demonstrated antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol (THC) in animals, but whether such synergy occurs against all types of pain and in humans is unclear. Because a majority of chronic pain patients are women, and sex differences in morphine and THC potencies have been observed in rodents, the present study examined sex-specific effects of morphine and THC given alone and in combination, in rats with persistent inflammatory pain. On Day 1, baseline mechanical and thermal response thresholds, hindpaw weight-bearing, locomotor activity, and hindpaw thickness were determined. Inflammation was then induced via hindpaw injection of complete Freund’s adjuvant (CFA). Three days later, morphine (s.c.), THC (i.p), or a morphine-THC combination (1:1, 3:1, and 1:3 dose ratios) was administered, and behavioral testing was conducted at 30-240 min post-injection. Morphine alone was anti-allodynic and anti-hyperalgesic, with no sex differences, but at some doses increased weight-bearing on the CFA-treated paw more in males than females. THC alone reduced mechanical allodynia with similar potency in both sexes, but reduced thermal hyperalgesia and locomotor activity with greater potency in females than males. All morphine-THC combinations reduced allodynia and hyperalgesia, but isobolographic analysis of mechanical allodynia data showed no significant morphine-THC synergy in either sex. Additionally, whereas morphine alone was antinociceptive at doses that did not suppress locomotion, morphine-THC combinations suppressed locomotion and did not increase weight-bearing on the inflamed paw. These results suggest that THC is unlikely to be a beneficial adjuvant when given in combination with morphine for reducing established inflammatory pain.

Adolescent cannabinoid exposure has been shown to alter cognitive, reward-related, and motor behaviors as well as mesocorticolimbic dopamine (DA) function in adult animals. Pain is also influenced by mesocorticolimbic DA function, but it is not known whether pain or cannabinoid analgesia in adults is altered by early exposure to cannabinoids.To determine whether adolescent ΔVehicle or THC (2.5 to 10 mg/kg s.c.) was administered daily to male and female rats on post-natal day (PND) 30-43. In adulthood (PND 80-88), sensitivity to mechanical and thermal stimuli before and after intraplantar injection of complete Freund's adjuvant (CFA) was determined. Antinociceptive, exploratory, and consummatory effects of 2.0 mg/kg THC were then examined.Adolescent THC exposure did not significantly alter adult sensitivity to non-noxious or noxious stimuli either before or after CFA injection, nor did it alter the antinociceptive effect of THC. In contrast, adolescent THC exposure altered adult exploratory and consummatory behaviors in a sex-dependent manner: when tested as adults, adolescent THC-treated males showed less hedonic drinking than adolescent vehicle-treated males, and females but not males that had been THC-exposed as adolescents showed reduced sensitivity to THC-induced suppression of activity and THC-induced hedonic drinking as adults.Adolescent THC exposure that altered both exploratory and consummatory behaviors in adults did not alter pain-related behaviors either before or after induction of inflammatory pain, suggesting that cannabinoid exposure during adolescence is not likely to substantially alter pain or cannabinoid analgesia in adulthood.

Given the use of cannabis as an analgesic by a broadening age range of patients, the aim of this study was to determine whether the antinociceptive effects of Δ9-tetrahydrocannabinol (THC) differ by age. The antinociceptive potency and efficacy of THC (1.0-18 mg/kg ip) was compared in male and female rats aged postnatal day 35-40 (adolescent), 60-70 (young adult), and 291-325 (middle-aged adult), using warm water tail withdrawal and paw pressure tests. Motoric effects of THC were assessed using a locomotor activity test. On the tail withdrawal test, THC was significantly more effective in middle-aged adult than in young adult rats and significantly less effective in adolescent than in young adult rats. Similar but smaller age-related differences were observed on the paw pressure test. Sex differences in THC's antinociceptive effects were consistent across the 3 ages examined, with greater THC effects observed in females than males of each age. Age-related differences in THC's locomotor-suppressing effect were also observed, with the greatest effect in young adult female rats. Serum THC levels were slightly higher in adolescent than in young adult rats, and levels of the active metabolites 11-OH-THC and cannabinol, as well as the inactive metabolite 11-nor-9-carboxy-THC, did not differ between adolescent and young adult rats. These results suggest that the pain-relieving effects of THC may be more limited in adolescents than in adults and that these age-related differences in THC effect are not attributable to differential absorption or metabolism of THC. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The primary aim of this study was to examine sex differences in acute antinociceptive and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in rats. Complete Freund’s adjuvant (CFA) was administered to adult Sprague–Dawley rats to induce pain and inflammation in one hindpaw; 2.5 h later, vehicle or a single dose of the NSAIDs ibuprofen (1.0–32 mg/kg) or ketoprofen (0.1–10 mg/kg), or the COX-2-preferring inhibitor celecoxib (1.0–10 mg/kg) was injected i.p. Mechanical allodynia, heat hyperalgesia, biased weight-bearing, and hindpaw thickness were assessed 0.5–24 h after drug injection. Ibuprofen and ketoprofen were more potent or efficacious in females than males in reducing mechanical allodynia and increasing weight-bearing on the CFA-injected paw, and celecoxib was longer-acting in females than males on these endpoints. In contrast, ketoprofen and celecoxib were more potent or efficacious in males than females in reducing hindpaw edema. When administered 3 days rather than 2.5 h after CFA, ketoprofen (3.2–32 mg/kg) was minimally effective in attenuating mechanical allodynia and heat hyperalgesia, and did not restore weight-bearing or significantly decrease hindpaw edema, with no sex differences in any effect. Neither celecoxib nor ketoprofen effects were significantly attenuated by cannabinoid receptor 1 or 2 (CB1 or CB2) antagonists in either sex. These results suggest that common NSAIDs administered shortly after induction of inflammation are more effective in females than males in regard to their antinociceptive effects, whereas their anti-inflammatory effects tend to favor males; effect sizes indicate that sex differences in NSAID effect may be functionally important in some cases.

Despite greater chronic pain prevalence in females compared with males, and the analgesic potential of cannabinoid receptor type 2 (CB2) agonists, CB2 agonists have rarely been tested in females. The aim of the present study was to compare the antinociceptive effects of a CB2-preferring agonist, (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone (JWH015), in female and male rats against acute pain and persistent inflammatory pain. JWH015 (5-20 mg/kg, intraperitoneally) produced dose-dependent and time-dependent increases in latency to respond on the tail withdrawal and paw pressure tests that did not differ statistically between the sexes. JWH015 dose-dependently decreased locomotor activity in both sexes, but was more potent in females than males. JWH015 produced little catalepsy in either sex. In females, the antinociceptive effects of JWH015 against acute pain were blocked by rimonabant and SR144528, whereas locomotor suppression was antagonized by rimonabant. When administered 3 days after intraplantar injection of complete Freund's adjuvant, JWH015 produced a significantly greater antiallodynic effect in females at the highest dose tested (10 mg/kg, intraperitoneally). Antiallodynic effects of JWH015 were antagonized by rimonabant and SR144528 in both sexes. These studies indicate that systemically administered JWH015 produced antinociception that was both CB1 and CB2 receptor-mediated in both sexes. Unlike [INCREMENT]-9-tetrahydrocannabinol and other nonselective cannabinoid agonists, the CB2-preferring agonist JWH015 may produce more equivalent antinociception in females and males.

Background The ability to effectively cope with stress is a critical determinant of disease susceptibility. The lateral habenula (LHb) and the endocannabinoid (ECB) system have independently been shown to be involved in the selection of stress coping strategies, yet the role of ECB signaling in the LHb remains unknown. Methods Using a battery of complementary techniques in rats, we examined the localization of type-1 cannabinoid receptors (CB1Rs) and assessed the behavioral and neuroendocrine effects of intra-LHb CB1R manipulations. We further tested the extent to which the ECB system in the LHb is impacted following chronic unpredictable stress or social defeat stress, and whether manipulation of LHb CB1Rs can bias coping strategies in rats with a history of chronic stress. Results Electron microscopy studies revealed CB1R expression on presynaptic axon terminals, postsynaptic membranes, mitochondria, and glial processes in the rat LHb. In vivo microdialysis experiments indicated that acute stress increased the amount of 2-arachidonoylglycerol in the LHb, while intra-LHb CB1R blockade increased basal corticosterone, augmented proactive coping strategies, and reduced anxiety-like behavior. Basal LHb 2-arachidonoylglycerol content was similarly elevated in rats that were subjected to chronic unpredictable stress or social defeat stress and positively correlated with adrenal weight. Finally, intra-LHb CB1R blockade increased proactive behaviors in response to a novel conspecific, increasing approach behaviors irrespective of stress history and decreasing the latency to be attacked during an agonistic encounter. Conclusions Alterations in LHb ECB signaling may be relevant for development of stress-related pathologies in which LHb dysfunction and stress-coping impairments are hallmark symptoms.

RATIONALE: Humans typically self-administer cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) together repeatedly (as in cannabis, cannabis extract, or Sativex®) to relieve pain. It has been suggested that one benefit of the drug combination may be decreased tolerance development. OBJECTIVE: The present study compared the development of tolerance to the antinociceptive effects of THC given alone versus combined with CBD, in rats. METHODS: THC dose-effect curves on tail withdrawal and paw pressure tests were obtained before and after twice-daily treatment with vehicle or CBD (10 mg/kg), plus vehicle or THC (3.6 mg/kg females; 9.3 mg/kg males) for 4 days. RESULTS: On the first day, THC was more potent in females than males on both nociceptive tests. From pre- to post-chronic (Day 1 to Day 6), THC potency on the tail withdrawal test decreased more in females than males, and rats that had been treated with CBD+THC repeatedly showed greater rightward/downward shifts of the THC dose-effect curve than rats that had been treated with THC alone. Analysis of blood samples taken after Day 6 testing showed that serum THC levels were higher in CBD+THC-treated females than in vehicle+THC-treated females, and THC’s active metabolite 11-OH-THC and its inactive metabolite THC-COOH were lower in CBD+THC-treated rats than in vehicle+THC-treated rats of both sexes. CBD also increased serum levels of the active metabolite cannabinol in both sexes. CONCLUSION: The decrease in THC’s antinociceptive effects after repeated CBD exposure may be due to CBD-induced inhibition of THC metabolism, and/or antagonism of THC effects that emerges with repeated CBD treatment.

The purpose of this study was to determine whether sex differences in the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol (THC) are due to activational effects of gonadal hormones. Rats were sham-gonadectomized (sham-GDX) or gonadectomized (GDX). GDX females received no hormone replacement (GDX + 0), estradiol (GDX + E2), progesterone (GDX + P4), or both (GDX + E2/P4). GDX male rats received no hormone (GDX + 0) or testosterone (GDX + T). Two weeks later, antinociceptive potency of THC was determined (pre-chronic test) on the warm water tail withdrawal and paw pressure assays. Vehicle or a sex-specific THC dose (females, 5.7 mg/kg, males, 9.9 mg/kg) was administered twice-daily for 9 days, then the THC dose–effect curves were re-determined (post-chronic test). On the pre-chronic test (both assays), THC was more potent in sham-GDX females than males, and gonadectomy did not alter this sex difference. In GDX females, P4 significantly decreased THC's antinociceptive potency, whereas E2 had no effect. In GDX males, T did not alter THC's antinociceptive potency. After chronic THC treatment, THC's antinociceptive potency was decreased more in sham-GDX females than males, on the tail withdrawal test; this sex difference in tolerance was not altered in GDX or hormone-treated groups. These results suggest that greater antinociceptive tolerance in females, which occurred despite females receiving 40% less THC than males, is not due to activational effects of gonadal hormones.

Background Previous studies suggest that cannabidiol (CBD) may potentiate or antagonize Δ9-tetrahydrocannabinol’s (THC) effects. The current study examined sex differences in CBD modulation of THC-induced antinociception, hypolocomotion, and metabolism. Methods In Experiment 1, CBD (0, 10 or 30 mg/kg) was administered 15 min before THC (0, 1.8, 3.2, 5.6 or 10 mg/kg), and rats were tested for antinociception and locomotion 15–360 min post-THC injection. In Experiments 2 and 3, CBD (30 mg/kg) was administered 13 h or 15 min before THC (1.8 mg/kg); rats were tested for antinociception and locomotion 30–480 min post-THC injection (Experiment 2), or serum samples were taken 30–360 min post-THC injection to examine CBD modulation of THC metabolism (Experiment 3). Results In Experiment 1, CBD alone produced no antinociceptive effects, while enhancing THC-induced paw pressure but not tail withdrawal antinociception 4–6 h post-THC injection. CBD alone increased locomotor activity at 6 h post-injection, but enhanced THC-induced hypolocomotion 4–6 h post-THC injection, at lower THC doses. There were no sex differences in CBD-THC interactions. In Experiments 2 and 3, CBD did not significantly enhance THC’s effects when CBD was administered 13 h or 15 min before THC; however, CBD inhibited THC metabolism, and this effect was greater in females than males. Conclusions These results suggest that CBD may enhance THC’s antinociceptive and hypolocomotive effects, primarily prolonging THC’s duration of action; however, these effects were small and inconsistent across experiments. CBD inhibition of THC metabolism as well other mechanisms likely contribute to CBD-THC interactions on behavior.

Chronic recreational marijuana users often report withdrawal symptoms when trying to quit, with some reports suggesting withdrawal may be more pronounced in women. In animal models, female rodents show enhanced sensitivity to acute Δ(9)-tetrahydrocannabinol (THC) administration, but chronic administration has been studied little.Sex differences in THC dependence in rats were examined. Adult male and female Sprague-Dawley rats were administered 30 mg/kg THC or vehicle twice daily for 6.5 days. On day 7, rats were challenged with vehicle or rimonabant, counterbalanced across dosing groups, and were assessed for withdrawal-related behaviors.During chronic THC dosing, disruption of estrous cycling and weight loss (both sexes) were observed. Whereas overt signs of withdrawal were minimal in THC-treated rats challenged with vehicle, rimonabant precipitated a pronounced withdrawal syndrome in THC-dependent rats that was characterized by changes in a number of domains, including somatic (paw tremors, head twitches, and retropulsion), early-stage cognition (lack of locomotor habituation, disrupted prepulse inhibition), and affective (increased startle reactivity). With the exception of increased retropulsion in female rats, sex differences were not noted. In vehicle-treated rats, rimonabant induced puritis.This study represents the first examination of THC dependence in adult rats of both sexes, extends previous findings to females, and revealed some sex differences. The results suggest that the changes that occur during precipitated withdrawal from THC extend beyond somatic signs to more nuanced disruptions of cognitive and affective functioning. The breadth of withdrawal signs observed in rodents mirrors those that have been observed in humans.

Women report greater sensitivity to the subjective effects of ΔA cumulative dosing THC discrimination procedure was utilized to evaluate sex differences in the discriminative stimulus effects of THC and three synthetic cannabinoids: CP47,497, WIN55,212-2, and JWH-018. Sex differences in the effects of these four compounds and a degradant of A-834735 on response rates also were assessed in a food-reinforced discrete dosing procedure.Females required a lower training dose than males for acquisition of the discrimination. Further, THC was more potent at producing rimonabant-reversible discriminative stimulus and response rate effects in females. While synthetic cannabinoids were more potent in producing THC-like effects than was THC in female rats, greater discrepancies were observed in male rats. Similar sensitivity to the response rate-decreasing effects induced by most, but not all (A-834735 degradant), synthetic cannabinoids was seen in both sexes.This study represents one of the first direct comparisons of sex differences in THC discrimination. Females were more sensitive to THC's effects, which may be related, in part, to sex differences in THC metabolism. Synthetic cannabinoids were more potent than THC in both sexes, but were considerably more so in male than in female rats. Future research should emphasize further characterization of sex differences in cannabinoid pharmacology.

Chronic intermittent alcohol (CIA) exposure produces altered motivational states characterized by anxiety and escalated alcohol consumption during withdrawal. The endocannabinoid (ECB) system contributes to these symptoms, and sex differences in alcohol dependence, as well as bidirectional interactions between ECBs and gonadal hormones have been documented. Thus, we evaluated sex differences in alcohol consumption, anxiety-like behavior, and ECB mRNA expression in the nucleus accumbens (NAc) of alcohol-dependent rats during acute withdrawal. Male rats exposed to six weeks of CIA showed escalated alcohol consumption during acute withdrawal and reductions in NAc N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD), DAG lipase alpha (DAGLα), and monoacylglycerol lipase (MAGL) mRNA. Intact alcohol-dependent female rats also escalated their consumption, but notably, this effect was also present in non-dependent females. No differences in NAc ECB mRNA were observed between CIA- and air-exposed females during acute withdrawal. However, when these data were analyzed according to estrous stage, significant differences in NAPEPLD and MAGL mRNA expression emerged in the NAc of air-exposed control rats, which were absent in alcohol-dependent females. We subsequently measured alcohol consumption and NAc ECB mRNA in ovariectomized (OVX) females with or without estradiol (E2) replacement during withdrawal. Neither E2 nor CIA altered alcohol consumption in OVX females. However, E2 reduced both DAGLα and MAGL mRNA, suggesting that E2 may influence the biosynthesis and degradation of 2-arachidonoylglycerol (2-AG) in the NAc. Collectively, these studies indicate sexual dimorphism in alcohol consumption in non-dependent rats and suggest that E2-mediated alterations in NAc ECB mRNA expression during withdrawal may be a mechanism by which sex differences in alcohol dependence emerge.

The purpose of this study was to determine whether sex differences in cannabinoid (CB)-induced antinociception and motoric effects can be attributed to differential activation of CB 1 or CB 2 receptors. Rats were injected intraperitoneally with vehicle, rimonabant [5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl- N -1-piperidinyl-1 H -pyrazole-3-carboxamide (SR141716A), a putative CB 1 receptor-selective antagonist; 0.1–10 mg/kg ] or 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]- N -[(1 S ,2 S ,4 R )-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1 H -pyrazole-3-carboxamide (SR144528) (a putative CB 2 receptor-selective antagonist; 1.0–10 mg/kg). Thirty minutes later, Δ 9 -tetrahydrocannabinol (THC; 1.25–40 mg/kg) or 5-(1,1-dimethylheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]phenol (CP55,940) (0.05–1.6 mg/kg) was injected. Paw pressure and tail withdrawal antinociception, locomotor activity, and catalepsy were measured. Rimonabant dose-dependently antagonized THC and CP55,940 in each test, but was up to 10 times more potent in female than male rats on the nociceptive tests; estimates of rimonabant affinity (apparent p K B ) for the CB 1 receptor were approximately 0.5 to 1 mol/kg higher in female than male rats. SR144528 partially antagonized THC-induced tail withdrawal antinociception and locomotor activity in females, but this antagonism was not dose-dependent or consistent; no SR144528 antagonism was observed in either sex tested with CP55,940. Neither the time course of rimonabant antagonism nor the plasma levels of rimonabant differed between the sexes. Rimonabant and SR144528 did not antagonize morphine-induced antinociception, and naloxone did not antagonize THC-induced antinociception in either sex. These results suggest that THC produces acute antinociceptive and motoric effects via activation of CB 1 , and perhaps under some conditions, CB 2 receptors, in female rats, whereas THC acts primarily at CB 1 receptors in male rats. Higher apparent p K B for rimonabant in female rats suggests that cannabinoid drugs bind with greater affinity to CB 1 receptors in female than male rats, probably contributing to greater antinociceptive effects observed in female compared with male rats.

Postpartum depression (PPD) is a debilitating illness, yet little is known about its causes. The purpose of this study was to examine a major symptom of depression during the postpartum period, anhedonia, by comparing sucrose preference in female rats that had undergone actual pregnancy or hormone-simulated pregnancy (HSP) to their respective controls. Whereas HSP rats showed significantly less preference than vehicle-control rats for 1% sucrose solution during the first three weeks of the “postpartum” period, previously pregnant females showed only slightly depressed sucrose preference for the first 1–2 days postpartum, compared to non-pregnant controls. Habituation to 1% sucrose during the pregnancy period, which increased preference upon later testing in previously pregnant rats tested on postpartum day 2, did not significantly increase preference in HSP rats, suggesting that depressed preference in the latter group was not due to neophobia. Pre-treatment with desipramine did not prevent suppressed sucrose preference in HSP rats, and preference was even further suppressed following chronic sertraline treatment. These results suggest that estradiol withdrawal following HSP may cause anhedonia during the early “postpartum” period. In contrast, females that have undergone actual pregnancy are less likely to show this effect, suggesting that postpartum hormonal changes other than the dramatic decline in estradiol may buffer its negative mood effects.

In September 2006, members of the Sex, Gender and Pain Special Interest Group of the International Association for the Study of Pain met to discuss the following: (1) what is known about sex and gender differences in pain and analgesia; (2) what are the "best practice" guidelines for pain research with respect to sex and gender; and (3) what are the crucial questions to address in the near future? The resulting consensus presented herein includes input from basic science, clinical and psychosocial pain researchers, as well as from recognized experts in sexual differentiation and reproductive endocrinology. We intend this document to serve as a utilitarian and thought-provoking guide for future research on sex and gender differences in pain and analgesia, both for those currently working in this field as well as those still wondering, "Do I really need to study females?"

Given the findings that (1) systemic opioid antinociception varies by estrous stage in females and (2) the magnitude of sex differences in opioid antinociception is negatively correlated with opioid agonist efficacy, we hypothesized that sex differences in the function of the descending pain modulatory system are likely influenced by estrous stage in females and by the number of available opioid receptors therein. The present study tested these hypotheses by (1) comparing antinociception produced by morphine microinjection to the ventral periaqueductal gray (vPAG) in females at different stages of the estrous cycle and (2) examining systemic morphine antinociception in males versus females under conditions of reduced vPAG mu opioid receptor availability. When estrous stage of females was not controlled for (Experiment 1), there was no significant sex difference in tail withdrawal antinociception following morphine microinjection (0.3-10microg), although morphine was more potent in males than females in producing immobility. Experiment 2 showed that intra-vPAG morphine produced less antinociception and immobility in estrus than in diestrus females; that is, only estrus females' response to morphine was lower than that of males. Experiment 3 showed that microinjection of the irreversible mu opioid antagonist beta-funaltrexamine (beta-FNA) into the vPAG shifted the systemic morphine dose-effect curve farther to the right in females than in males. That is, a reduction in available vPAG mu opioid receptors had a greater impact on opioid antinociception in females than in males, suggesting that females have fewer vPAG mu opioid receptors than males. Overall, these data suggest that ovarian hormones and PAG mu opioid receptor density contribute to sex differences in antinociception produced by morphine.

Cannabis is the most widely used illicit substance in the United States. Women report greater positive subjective effects of cannabis, and greater cannabis withdrawal compared to men. Female rodents are more sensitive than males to some acute effects of Δ⁹-tetrahydrocannabinol (THC), and females also develop greater tolerance to THC in some assays. The purpose of this study was to determine whether gonadal hormones modulate THC dependence in rats. Adult rats were gonadectomized (GDX) or sham-GDX, and hormone was replaced in half of the GDX rats of each sex (testosterone in males; estradiol and/or progesterone in females). THC (30 mg/kg) or vehicle was administered twice daily for 6.5 days, followed on the seventh day by vehicle or rimonabant challenge and assessment for withdrawal-related behaviors. Sham-GDX females developed greater tolerance than males to THC-induced hypothermia, and GDX females given progesterone showed greater tolerance to THC-induced locomotor suppression. Rimonabant precipitated withdrawal, as evidenced by increased somatic signs (forepaw tremors, licking) and increased startle amplitude. Testosterone in GDX males decreased withdrawal-induced licking. Estradiol and progesterone in GDX females increased withdrawal-induced chewing, and progesterone increased withdrawal-induced sniffing. These results suggest that estradiol and progesterone may promote the development of dependence, whereas testosterone may protect against dependence. While the present study indicates that testosterone and estradiol produce opposite effects on THC-induced behavior, estradiol appears to play a broader role than testosterone in modulating THC's behavioral effects.

Sex differences in reinforcing, analgesic and other effects of opioids have been demonstrated; however, the extent to which sex differences in motoric effects of opioids contribute to apparent sex differences in their primary effects is not known. The goal of this study was to compare the effects of the prototypic mu opioid agonist morphine on locomotor activity in male vs. female rats. Saline or morphine (1-10 mg/kg) was administered s.c. to adult Sprague-Dawley rats, which were placed into a photobeam apparatus for 3-5 hr to measure activity. Modulation of morphine's effects by gonadal hormones and by handling (either during the test session or for 4 days before the test session) were examined. Morphine initially suppressed and later increased locomotor activity in both sexes relative to their saline-injected controls, but males were more sensitive than females to the initial locomotor suppressant effect of morphine. Intermittent, brief handling during the 3-hr test session blunted morphine-induced locomotor activation in both sexes. Females in proestrus were the most sensitive to morphine's locomotor-stimulant effect, with females in estrus showing the least response to morphine. Gonadectomized (GDX) males with or without testosterone were equally sensitive to morphine's effects, whereas GDX females treated with estradiol showed a blunted response to morphine's effects, similar to intact females in estrus. Brief handling on each of 4 consecutive days pre-test attenuated morphine's locomotor suppressant effect in males but had no effect in females, thereby eliminating the sex difference. These data suggest that sex differences in morphine's effects on locomotor activity can be attributed to gonadal hormones in females, and to differential stress-induced modulation of morphine's effects in males vs. females.

Previous studies have produced mixed results about the role of the ventral tegmental area, periaqueductal gray and parabrachial nucleus in morphine discriminations, perhaps owing to the considerably different methodologies used. The purpose of the present study was to compare the roles of these three brain areas using the same food-reinforced discrimination protocol, to determine whether the schedule of reinforcement influenced maximal substitution produced by site-specific morphine administration and to determine whether the time course of substitution differed by site of morphine administration. Rats were trained to discriminate 3.0 mg/kg subcutaneous morphine from saline under variable interval 15-s or fixed ratio 10 schedules of food reinforcement. Rats were then implanted with one cannula aimed at the lateral ventricle (intracerebroventricular) and one aimed at the ventral tegmental area, periaqueductal gray or parabrachial nucleus. Morphine discrimination curves were obtained by subcutaneous, intracerebroventricular and intrasite routes. When administered subcutaneously, morphine was equipotent in variable interval-trained and fixed ratio-trained rats, although it was more potent in fixed ratio-trained females than fixed ratio-trained males. When administered intracerebroventricularly, morphine (0.3-10 microg) engendered a maximum average of 63% drug-appropriate responding in both variable interval-trained and fixed ratio-trained rats; females showed significantly greater drug-appropriate responding than males, again under the fixed ratio but not under the variable interval schedule. In variable interval-trained rats, intrasite infusions of morphine (0.3-10 microg) produced maximal drug-appropriate responding of approximately 57% (ventral tegmental area), 56% (periaqueductal gray) and 41% (parabrachial nucleus); mean maximal substitution was slightly (< or = 17%) greater in fixed ratio-trained rats. When injected into the ventral tegmental area or periaqueductal gray, but not the parabrachial nucleus, naloxone methiodide (2 microg) significantly decreased drug-appropriate responding following 3.0 mg/kg subcutaneous morphine, in both variable interval-trained and fixed ratio-trained rats. The time course of the discriminative stimulus effects of morphine differed among the three brain sites: intraventral tegmental area morphine produced peak drug-appropriate responding by 15 min after injection, whereas the discriminative stimulus effects of intraperiaqueductal gray and intraparabrachial nucleus morphine peaked at approximately 60 min after injection. Taken together, these results indicate that ventral tegmental area, periaqueductal gray and parabrachial nucleus each play a role in the ability of morphine to function as a discriminative stimulus, regardless of the sex of the subject or the schedule under which the subjects are responding. Ventral tegmental area and periaqueductal gray, however, appear to be more critical than parabrachial nucleus in mediating the discriminative effects of systemic morphine in rats responding under a food reinforcement procedure. The pretreatment time and, to a lesser extent, the schedule of reinforcement are additional variables that should be considered when comparing the relative roles of different brain areas in drug discrimination.

Previous studies suggest that sex differences in morphine antinociception in rodents might be attributed to the activational effects of gonadal hormones. The present study determined whether hormonal modulation of opioid antinociception in adult rats extends to opioids other than the prototypic mu agonist morphine. Male and female rats were sham-gonadectomized (sham-GDX) or gonadectomized (GDX) and replaced with no hormone, estradiol (E2, females), progesterone (P4, females), E2+P4 (females), or testosterone (males). Approximately 28 days later, nociception was evaluated on the 50°C hot plate and warm water tail withdrawal tests before and after subcutaneous administration of hydromorphone, buprenorphine, U50,488, or SNC 80. In sham-GDX (gonadally intact) rats, the mu agonists and U50,488 were less effective in females than in males in at least one nociceptive test, and the delta agonist SNC 80 was less effective in males than in females. In males, gonadectomy tended to decrease, and testosterone tended to increase antinociception produced by 3 of the 4 agonists. In females, gonadectomy and hormone treatment had more variable effects, although E2 tended to decrease mu opioid antinociception. The present results suggest that activational effects of gonadal hormones are relatively modest and somewhat inconsistent on antinociception produced by various opioid agonists in the adult rat. Perspective This study demonstrates that reproductive hormones such as testosterone in males and estradiol in females do not consistently modulate sensitivity to the analgesic effects of opioids in the adult organism.

NMDA antagonists may be useful for their potential to increase or prolong opioid analgesia while attenuating the development of opioid tolerance and dependence. The purpose of this study was to determine whether there are sex differences in NMDA antagonist modulation of morphine antinociception. Adult female and male Sprague–Dawley rats were injected s.c. with saline or one dose of MK-801 (0.005, 0.01, 0.02, or 0.04 mg/kg), dextromethorphan (5, 10, or 20 mg/kg), or LY235959 (0.5, 1.0, or 2.0 mg/kg) in combination with saline or one dose of morphine (1.8, 3.2, or 5.6 mg/kg), and tested on the 50 °C hotplate and tail withdrawal assays 15–120 min post-injection. At the doses examined, only LY235959 produced any antinociception when administered alone. MK-801 attenuated morphine antinociception on both assays, but only at sporadic (inconsistent) dose-combinations. Dextromethorphan increased morphine antinociception on the hotplate but not tail withdrawal assay, at all three morphine doses in males, but only the higher morphine doses in females. In contrast, LY235959 modulated morphine antinociception on both assays; the lowest dose attenuated, and higher doses enhanced morphine antinociception, but the particular morphine doses and assay in which these effects occurred depended on the sex of the subject. Thus, all three NMDA antagonists modulated morphine antinociception in female and male rats, but the direction of this modulation depended on the particular antagonist examined, the nociceptive test, the dose of antagonist and of morphine, and time post-injection.

Cannabinoids have been shown to produce greater behavioral effects in female than in male rats. Sex differences in the metabolism of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) have also been demonstrated in one study. The goal of this study was to determine if sex differences in Delta(9)-THC disposition or metabolism could explain sex differences in Delta(9)-THC-induced behavioral effects. [(3)H]-Delta(9)-THC was administered intraperitoneally (i.p.) to rats and the presence of [(3)H]-Delta(9)-THC and metabolites in serum and brain tissue were compared at multiple times post-injection in male versus female rats. Serum levels of Delta(9)-THC and its metabolites were similar in males and females. In brain tissue, [(3)H]-Delta(9)-THC levels also were similar in males and females. In contrast, levels of Delta(9)-THC metabolites in brain tissue, including 11-hydroxy-Delta(9)-THC, the major active metabolite, were higher in females than in males. To further investigate if greater production of active metabolites by females explained the greater Delta(9)-THC-induced behavioral effects observed in females, i.p. Delta(9)-THC-induced antinociception (50 degrees C warm water tail withdrawal assay) and catalepsy (bar test) were compared in male and female rats following pretreatment with saline or SKF525A, a cytochrome P450 inhibitor. SKF525A did not affect basal responding in the tail withdrawal assay or bar test in either sex. SKF525A significantly attenuated Delta(9)-THC-induced antinociception only in females. A similar sex difference was observed in the effects of SKF525A on Delta(9)-THC-induced catalepsy. These results suggest that the greater levels of active Delta(9)-THC metabolites produced by females contribute to greater behavioral effects of Delta(9)-THC in female compared to male rats.

Cannabinoids have been shown to produce greater behavioral effects in female than male rats. Although central nervous system CB(1) receptors are known to mediate cannabinoid-induced behavioral effects in male rats, it is not known whether the same is true for females.To determine if cannabinoid-induced antinociception and catalepsy are similarly mediated by central CB(1) receptors in male and female rats.The ability of SR141716A, a CB(1) receptor selective antagonist, administered ICV (1-1000 microg) or IT (1-600 microg) to block 10 mg/kg IP delta(9)-THC-induced antinociception (paw pressure) and catalepsy (bar test), was compared in male and female rats.Delta(9)-THC alone produced slightly greater antinociception, and significantly greater catalepsy in females than males. When administered ICV, SR141716A partially antagonized delta(9)-THC-induced antinociception in both females and males. IT SR141716A also antagonized delta(9)-THC-induced antinociception in both sexes; it was slightly more potent in males but equally effective in males and females. SR141716A antagonized delta(9)-THC-induced catalepsy in a similar manner in males and females when given ICV or IT.These results confirm that delta(9)-THC-induced behavioral effects are mediated by central CB(1) receptors in male and female rats.

Historically, biomedical research has been conducted almost exclusively with male subjects. A growing number of studies now demonstrate sex differences in analgesia produced both by drugs and by environmental stimuli. This review summarizes the current literature on sex differences in analgesia produced by opioids, cholinergics and other drugs, and by stress, exercise and other environmental manipulations. A brief overview of the physiological mechanisms underlying sex differences in analgesia is provided, as well as suggestions for future research. It is not yet known whether the development of sex-specific analgesia treatment guidelines is warranted.

Background Numerous experimental studies, conducted primarily over the past 10 years, show that there are sex differences in opioid analgesia. This review summarizes the published literature on sex differences in analgesia produced by acute administration of drugs acting at mu-, kappa-, and delta-opioid receptors, in animals and humans. Additionally, methodological issues in research into opioid sex differences are discussed. Conclusions Procedural variables that may influence the outcome of studies examining sex differences in opioid analgesia include modality and intensity of the noxious stimulus used in the pain test, opioid type (efficacy and selectivity), and experimental design and data analytic techniques. Subject variables that may be important to consider include subject genotype and gonadal steroid hormone state of the subject at the time of analgesia testing. Evidence is provided for multiple mechanisms underlying sex differences in opioid analgesia, including both pharmacokinetic and pharmacodynamic factors. Future research directions are suggested, such as examining sex differences in opioid tolerance development, sex differences in opioid analgesia using models of acute inflammatory pain and chronic pain, and sex differences in effects of opioids other than analgesia, which may limit their therapeutic use.

To determine whether sex differences in the effects of mixed-action opioids could be due to differential activity at mu or kappa receptors, agonist/antagonist properties of nalbuphine, butorphanol and (-)-pentazocine were compared in male vs. female rats using a diuresis test. In water-loaded rats (2-h test), nalbuphine and (-)-pentazocine dose-dependently increased urination similarly in both sexes, whereas butorphanol increased urination more in females than in males on a ml/kg basis. The diuretic effects of all three opioids were at least partially blocked by the kappa receptor-selective antagonist nor-binaltorphimine (nor-BNI, 5 mg/kg) in both sexes. Kappa receptor-mediated antagonism of diuresis induced by U69,593 (0.56 mg/kg) was only observed with butorphanol in males. In water-loaded rats (1-h test), nalbuphine did not suppress, and butorphanol and (-)-pentazocine significantly suppressed urination in males only; all three mixed-action opioids dose-dependently blocked the antidiuretic effect of the selective mu agonist fentanyl (0.056 mg/kg) in both sexes. The ability of nalbuphine and (-)-pentazocine to block fentanyl-induced antidiuresis was not affected by pretreatment with nor-BNI in either sex. In contrast, the ability of butorphanol to block fentanyl-induced antidiuresis was attenuated by pretreatment with nor-BNI in males but not in females. These results suggest that sex differences in the effects of these mixed-action opioids are primarily due to their greater relative efficacy at the mu receptor in male than in female rats; butorphanol also may have greater efficacy at kappa receptors in females than in males.

Sex differences in cannabinoid effects have been reported in rodents, with adult females typically being more sensitive than adult males. The present study compared the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol (THC) in adult, gonadally intact female vs. male rats.Cumulative dose-effect curves were obtained for THC (1.0-18 mg/kg i.p.) on warm water tail withdrawal and paw pressure tests. Vehicle or the sex-specific ED80 dose for THC was administered twice daily for 9 days; THC dose-effect curves were then re-determined.On the pre-chronic test day, THC was significantly more potent in females than males in producing antinociception on the tail withdrawal and paw pressure tests. After 9 days of twice-daily THC treatment (5.4 mg/kg/injection in females and 7.6 mg/kg/injection in males), THC potency on both tests decreased more in females than males. On the tail withdrawal test, chronic THC produced 4.2- vs. 2.8-fold increases in ED50 values in females vs. males, respectively. On the paw pressure test, chronic THC produced 4.4- vs. 2.9-fold increases in ED50 values in females vs. males, respectively. Chronic THC treatment did not significantly disrupt estrous cycling in females.These results demonstrate that--even when sex differences in acute THC potency are controlled--females develop more antinociceptive tolerance to THC than males. Given the importance of drug tolerance in the development of drug dependence, these results suggest that females may be more vulnerable than males to developing dependence after chronic cannabinoid exposure.

This study was conducted to determine whether sex differences in opioid antinociception may be explained by sex differences in opioid receptor activation. The time course, dose-effect and selectivity of antagonists that have been previously shown to be relatively mu (beta-funaltrexamine, beta-FNA), kappa (norbinaltorphimine, norBNI), or delta (naltrindole, NTI) receptor selective in male animals were compared in female and male Sprague-Dawley rats using a 52 degrees C hotplate test. In both sexes, beta-FNA (10 or 20 microg intracerebroventricularly [i.c.v.]) dose-dependently blocked the antinociceptive effects of fentanyl (0.056 mg/kg subcutaneously); antagonism was observed 24 h after beta-FNA, and diminished within 7-14 days. In both sexes, norBNI (1 or 10 microg i.c.v.) dose-dependently blocked the antinociceptive effects of U69,593 (1.0 mg/kg subcutaneously); antagonism was maximal by 1-3 days post-norBNI and lasted longer than 56 days. NTI (1 or 10 microg i.c.v.) dose-dependently blocked the antinociceptive effects of [D-Pen2, D-Pen5]enkephalin (DPDPE, 100 nmol i.c.v.) in both sexes; however, the duration of action of NTI was shorter in females than in males. The antinociceptive effects of the mu receptor-preferring agonists fentanyl, morphine and buprenorphine were significantly and dose-dependently antagonized by beta-FNA, but not by norBNI or NTI, in both sexes. Beta-FNA antagonism was significantly greater in females compared with males given morphine, but not fentanyl or buprenorphine. The antinociceptive effects of the kappa receptor-preferring agonists U69,593 and U50,488 were significantly and dose-dependently antagonized by norBNI; U50,488 but not U69,593 was also antagonized to a lesser extent by NTI and beta-FNA, in both sexes. The antinociceptive effect of the delta receptor-preferring agonist SNC 80 was significantly antagonized by NTI, but not by norBNI or beta-FNA, in both sexes. The sex difference in beta-FNA antagonism of morphine suggests that there may be sex differences in functional mu opioid receptor reserve or signal transduction; however, the lack of consistency across all mu agonists weakens this hypothesis. Overall, the opioids tested had very similar receptor selectivity in male and female subjects.

Rationale: Several investigators have shown that male rodents are more sensitive than females to morphine’s antinociceptive effects. Objective: The present study was conducted to determine whether this sex difference is stable after chronic morphine treatment. Results: Acutely administered morphine produced significantly greater hotplate and tail withdrawal antinociception in males than in females. In contrast, there were no sex differences in morphine’s hotplate or tail withdrawal effects under repeated (1-week interval) dosing conditions. In a separate group of rats, after 2 weeks of twice-daily morphine treatment (10–20 mg/kg per injection), the ED50 for morphine’s antinociceptive effects increased approximately 6.9-fold in males versus only 3.7-fold in females; chronic morphine treatment also disrupted the estrous cycle of females. In a separate group of rats treated with 10 mg/kg morphine twice daily for 5 days, treatment with naloxone (1.0 mg/kg) on day 6 produced greater withdrawal scores in males than in females. Conclusions: These experiments demonstrate sex differences in development of tolerance to and dependence on morphine in the rat.

The antinociceptive and locomotor effects of microinjecting morphine into the rostral ventromedial medulla (RVM) of male and female rats was assessed. Male rats showed greater antinociception than female rats at all doses and times following morphine administration. Male, but not female rats, also showed a dose dependent decrease in locomotion. These data demonstrate that sex differences in antinociception are mediated at least in part by the RVM.

This study examined cannabinoid-opioid interactions within the same subjects on measures of discrimination, antinociception, horizontal locomotion, and catalepsy. Male Sprague-Dawley rats were trained to discriminate Δ(9)-tetrahydrocannabinol (THC, 3 mg/kg) from vehicle. THC alone (0.32-10 mg/kg) dose-dependently increased THC-appropriate lever responding and decreased response rate. THC alone also produced paw pressure antinociception and decreased locomotor activity, but did not produce catalepsy. Methadone (0.32-5.6 mg/kg) and naltrexone (0.32-3.2 mg/kg) alone produced low THC-appropriate lever responding up to doses that decreased response rate. When combined with THC, methadone (1.0 mg/kg) flattened the THC discrimination curve, but did not affect antinociceptive or motoric effects of THC. Naltrexone did not alter any effects of THC. In rats that were not trained to discriminate THC from vehicle, 1.0 mg/kg methadone did enhance THC antinociception. These results suggest that μ-opioid receptor agonists can disrupt the discriminative stimulus effects of cannabinoids while not significantly altering their antinociceptive or motoric effects, in chronically drug-exposed subjects. Further research is required to determine whether opioid enhancement of cannabinoid antinociception is limited to acute exposure, or simply requires higher doses in chronically drug-exposed subjects.

To determine whether a mu opioid agonist modulates the effects of a kappa opioid agonist in squirrel monkeys responding under a shock titration procedure, morphine was administered in combination with an ED75 dose of U50,488. Morphine (0.03-0.3 mg/kg) did not alter U50,488's early peak effects (15-25 min post-injection), but dose dependently antagonized U50,488's later effects (40-100 min post-injection); these doses of morphine shifted the U50,488 dose-effect curve1/4 log unit to the right. After 6-8 weeks of daily morphine administration, higher doses of morphine (0.3-3.0 mg/kg) shifted the U50,488 dose-effect curve1/2 log unit to the right. Morphine still did not antagonize early peak effects of the ED75 dose of U50,488, but antagonized early and late effects of a lower dose. Thus, morphine is a weak kappa antagonist in the shock titration procedure. In addition to its low affinity for kappa receptors, morphine's kappa antagonist activity is limited by its mu agonist effects, particularly in the non-morphine-tolerant monkey.

The purpose of this study was to investigate the effects of acute and chronic administration of anabolic–androgenic steroids (AAS) on nociception and morphine antinociception in acute pain models, as well as on chronic inflammatory nociception. In Experiment 1, adult, gonadally intact male rats were injected s.c. for 28 days with either 5 mg/kg testosterone (T), dihydrotestosterone (DHT), stanozolol (STAN), or safflower oil vehicle (N = 12–25/group). On day 28, rats in each group were tested on acute thermal and mechanical nociceptive assays, before and after morphine treatment. In Experiment 2, rats in each group (N = 8–10/group) were injected with mineral oil or complete Freund's adjuvant (CFA) into one hindpaw after 28 days of AAS treatment, and then tested for thermal hyperalgesia, mechanical allodynia, inflammation and locomotor suppression intermittently for 28 days. Experiment 3 replicated nociceptive measurements in Experiments 1 and 2, but with a single AAS or vehicle injection occurring 3 h prior to testing (N = 10–12/group). While chronic AAS administration tended to decrease body weight gain and alter reproductive organ weights in the expected manner, it did not significantly alter acute nociception nor attenuate the development of various chronic pain indices after CFA administration. Morphine antinociceptive potency was significantly decreased by chronic DHT on the hotplate test only. Acute AAS administration also did not significantly alter acute or chronic nociception, or morphine antinociceptive potency. Comparisons between acute and chronic AAS administration suggest that steroid tolerance did not occur in rats treated with AAS chronically. Taken together, these data do not support the hypothesis that AAS exposure alters nociception or morphine antinociception in gonadally intact males.

Systemically administered cannabinoids produce greater antinociceptive and sedative effects in female compared to male rats. Sex differences in the brain endocannabinoid system have also been reported. The aim of this study was to determine whether sex differences in antinociceptive and motoric effects of a cannabinoid can be attributed to supraspinal mechanisms. Vehicle or Δ⁹-tetrahydrocannabinol (THC, 100 μg) was administered i.c.v., and behavioral effects were compared between gonadally intact male and female rats, and among females in different estrous stages (early proestrus, late proestrus, estrus and diestrus). Antinociception on the tail withdrawal and paw pressure tests after i.c.v. THC was slightly but not significantly greater in females (pooled across estrous stages) compared to males. THC suppressed locomotor activity similarly in all groups, with the exception that only males showed hyperlocomotion at 4 h post-injection. When females in the four estrous stages were compared, females in late proestrus showed significantly greater THC-induced antinociception than females in estrus (and males). These results suggest that supraspinal mechanisms may contribute to greater systemic THC effects in females compared to males, and to estrous stage-dependent differences in THC effects among females.

Background: It has been suggested that sexual differentiation of opioid analgesic sensitivity may parallel sexual differentiation in reproductive systems. Objective: The present study compared organizational and activational roles of testosterone in sexual differentiation in reproductive versus opioid antinociceptive systems in the rat, to assess whether both systems were similarly testosterone dependent. Methods: Male rat pups (Sprague-Dawley and Fisher 344 [F344]) were either handled or castrated on postnatal day (PND) 1, and female pups were injected with testosterone propionate (100 or 1000 µg) on PND 2. In adulthood, all rats were gonadectomized (or simply anesthetized) and implanted with either testosterone filled or blank capsules (one 10-mm capsule/100 g of body weight). Results: Two hundred one Sprague-Dawley rats and 178 F344 rats were used. In gonadally intact adults of both rat strains, the antinociceptive potency of subcutaneously injected morphine was significantly greater in males than in females ( P = 0.05). These sex differences were eliminated by neonatal castration in males or by neonatal androgenization in females. However, adult testosterone treatment reversed the effects of neonatal castration in males. Masculinization and defeminization of sexual behavior, ovary weight, and body weight generally met conventional expectations. Compared with male controls, neonatally castrated males gained less body weight, and displayed more lordosis behavior and compromised male sexual behaviors. Compared with female controls, neonatally androgenized females gained more body weight, developed smaller ovaries, and presented less lordosis behavior and more male sexual behaviors. Overall, neonatal testosterone manipulations sufficient to masculinize or defeminize rats in terms of reproductive behavior and physiology also masculinized or defeminized morphine antinociceptive sensitivity. The effects of neonatal castration were reversed by adult testosterone treatment, indicating that sexual differentiation of opioid antinociceptive systems begins before PND 1. Conclusions: Sensitivity to opioid antinociception begins to diverge between males and females early in life. The relationship between gonadal hormone-mediated sexual differentiation of the reproductive and the opioid antinociceptive systems suggests that the 2 systems may be functionally linked. This finding has implications for the treatment of pain and analgesia in women and men.

This review summarizes evidence for sex differences in behavioral effects of opioids, primarily in rats. Whereas micro agonists have been found to be more potent and in some cases more efficacious in producing analgesia and sedation in males than females, females are more sensitive than males to reinforcing and locomotor stimulant effects of opioids. Sex differences in motoric effects of opioids may contribute to sex differences in other behavioral effects of opioids; for example, sex differences in rats' ability to discriminate morphine from saline can be attributed entirely to greater morphine-induced sedation in males. Chronic estradiol blunts females' sensitivity to morphine's analgesic and sedative effects, but enhances females' sensitivity to the reinforcing and locomotor stimulant effects of micro opioids. The neurobiological basis for sex differences in and estradiol modulation of behavioral effects of opioids includes brain opioid receptor density (greater in males and under low-estradiol conditions in females) and dopaminergic function (greater in females and under high-estradiol conditions). Given the significant and growing use of opioids by women, both medicinally and recreationally, understanding how female biology influences analgesic and other effects of opioids is crucial.

The purpose of the present investigation was to characterize the mu agonist and kappa antagonist effects of the mixed opioid agonist/antagonist butorphanol. To this end, the effects of butorphanol were examined: 1) alone and in combination with the kappa agonist bremazocine in nontolerant and morphine-tolerant rats responding under a fixed-ratio 30 (FR30) schedule of food presentation, and 2) in rats trained to discriminate 10 mg/kg morphine from saline. Prior to the induction of morphine tolerance, morphine, bremazocine and butorphanol produced dose-dependent decreases in rate of responding under the FR30. In these nontolerant rats, butorphanol failed to antagonize bremazocine's rate-decreasing effects. During the chronic morphine regimen, the dose-effect curve for morphine was shifted to the right of its prechronic position by approximately 0.9 log units, whereas the bremazocine curve was not altered substantially. The butorphanol dose-effect curve, in contrast, was shifted to the right and flattened such that doses which eliminated responding in nontolerant rats, as well as doses approximately 1.0 log unit higher, had no effect on responding. In these morphine-tolerant rats, butorphanol produced a dose-dependent antagonism of bremazocine's rate-decreasing effects. In rats trained to discriminate morphine from saline, butorphanol substituted completely for the morphine stimulus. Unlike morphine, which produced its stimulus effects only at doses that decreased rate of responding, butorphanol substituted for the morphine stimulus at doses that had little or no effect on rate of responding.(ABSTRACT TRUNCATED AT 250 WORDS)

Female rats are more sensitive than males to many behavioral effects of cannabinoids. The purpose of the present study was to determine if sex differences in the antinociceptive and motoric effects of Delta(9)-tetrahydrocannabinol (THC) are due to activational effects of gonadal steroid hormones. THC-induced antinociception (tail withdrawal, paw pressure tests) and motoric effects (horizontal locomotion, catalepsy) were compared in male and female gonadectomized rats that were chronically treated with hormone (testosterone in males, estradiol in females) vs. those that were gonadectomized and had no hormone replacement. THC's effects were also compared between gonadally intact females tested during vaginal estrus vs. diestrus. THC (5 and 10 mg/kg i.p.) produced very similar antinociceptive effects in no-hormone vs. testosterone-treated males, but significantly less locomotor suppression in testosterone-treated males than those with no hormone replacement. In gonadectomized females, estradiol enhanced THC's antinociceptive but not motoric effects. In gonadally intact, cycling females, 5 mg/kg THC produced slightly to significantly greater behavioral effects in estrous than in diestrous females. These results suggest that sex differences in THC-induced behavioral effects in the adult rat can be attributed to activational effects of testosterone in males and/or estradiol in females.

To clarify the activational role of ovarian hormones on pain and analgesia, the present study determined whether estradiol (E2) modulation of nociception and morphine antinociception in adult female rats depends on (1) the dose of E2 and (2) the interval between E2 treatment and nociceptive testing. Female rats were ovariectomized (OvX) and either oil vehicle (0), or E2 (0.25, 2.5 or 25 microg/0.1 ml vehicle) was injected s.c. two consecutive days of every four days for five cycles before testing. Either 4, 24, 48 or 96 h after the last injection, nociception was evaluated on the 50 degrees C hotplate and warm water tail withdrawal tests before and after escalating doses of s.c. morphine. Lordosis behavior and uterine weight were assessed in other rats at the same E2 doses and time points. E2 significantly lengthened latency to respond on the hotplate test at 24 h after the last injection, but had no significant effect on tail withdrawal latencies. The lower doses of E2 significantly increased morphine antinociceptive potency at 4-24 h on one or both tests, but the intermediate E2 dose significantly decreased morphine potency at 48 h on the hotplate test. Thus, E2 modulation of morphine antinociception in the adult female rat is bidirectional, and occurs at E2 doses producing cyclic changes in sexual behavior, uterine weight and vaginal cytology that are similar to those observed in gonadally intact, cycling females.

The purpose of this study was to determine whether testosterone (T) concurrently modulates reproductive and nociceptive systems in the adult male. Male Sprague–Dawley rats were orchidectomized, and then 28 days later implanted with capsules containing T or nothing (blanks). After 2, 7, 14 or 28 days' exposure to T-filled or blank capsules, rats were tested for male sexual and nociceptive behaviors in a counter-balanced design. As the duration of T exposure lengthened, the percentage of rats showing male sexual behaviors and the weights of steroid-sensitive organs systematically increased, and latencies to show sexual behaviors decreased. T treatment did not affect basal nociception on either the hotplate or tail withdrawal tests, but significantly increased morphine's antinociceptive potency on the tail withdrawal test — however, this effect was small, and independent of duration of T exposure. Thus, T treatment that altered male sexual behavior and reproductive physiology in a systematic, duration-dependent manner did not similarly alter basal nociception or morphine antinociception. These findings suggest that in adult male rats, although T may modulate both male sexual behaviors and opioid antinociceptive sensitivity, these T effects do not occur in concert.

It has been shown previously that female rats are more sensitive than males to barbiturate anesthesia, whereas males may be more sensitive than females to opioid antinociception. The aim of the present study was to determine whether enhancement of morphine antinociception by pentobarbital, previously demonstrated in male animals and humans, occurs similarly in females. Pentobarbital (50 mg/kg i.p.) produced longer-lasting anesthetic effects (loss of muscle tone, righting reflex) in gonadally intact female rats than in males, but greater antinociceptive effects in males at some time points post-injection. There were no significant sex differences in morphine-induced anesthesia or antinociception; however, 50 mg/kg pentobarbital produced greater leftward shifts in the morphine antinociceptive dose-effect curve in gonadally intact females than males, whether pentobarbital was administered 30 vs. 120 min before morphine (times at which there were no sex differences vs. sex differences, respectively, in pentobarbital's effects when administered alone). Dose-addition analysis confirmed that pentobarbital enhancement of morphine antinociception was supra-additive in both sexes; morphine also significantly enhanced pentobarbital-induced anesthesia in both sexes. In gonadectomized males, testosterone did not significantly alter pentobarbital enhancement of morphine antinociception; in contrast, in gonadectomized females, estradiol significantly attenuated the drug interaction. Estradiol did not significantly alter the effects of pentobarbital alone or morphine alone, indicating that the attenuation of the pentobarbital's potentiation of morphine antinociception in estradiol-treated rats is specific to the drug interaction. These results suggest that barbiturate potentiation of opioid antinociception may be greater in females - particularly those in low ovarian hormone states - than in males.

This review summarizes the existing literature on sex differences in the effects of cannabinoid drugs on behavior, primarily in the adult rodent. These preclinical studies, taken together with preliminary reports of sex differences in cannabinoid effects in humans, suggest that sex of subject may be an important modulating factor in a variety of cannabinoid effects. When sex differences are found, females are usually more sensitive than males to cannabinoids. Both pharmacokinetic and pharmacodynamic variables may contribute to sex differences in behavioral effects of cannabinoids. Given the significant therapeutic potential of cannabinoid agonists and antagonists--as well as their widespread recreational use--it will be important to determine the reliability and functional significance of, as well as mechanisms underlying sex differences in cannabinoid effects.

There is now strong evidence for sex differences in pain and analgesia. These differences imply that gonadal steroid hormones such as estradiol and testosterone modulate sensitivity to pain and analgesia. The goal of this review is to present an overview of gonadal steroid modulation of pain and analgesia in animals and humans, and to describe mechanisms by which males' and females' biology may differentially predispose them to pain and to analgesic effects of drugs and stress. Evidence is presented to demonstrate that sex differences in pain and analgesia may be both quantitative and qualitative in nature. Current research suggests that sex-specific management of clinical pain will be a reality in the not-so-distant future.

The purpose of this study was to examine how gonadal steroid hormones modulate basal nociception and morphine antinociception relative to regulating reproduction in the adult rat. Male and female Sprague-Dawley rats were either gonadectomized (GDX) or sham-gonadectomized (sham); GDX males were implanted subcutaneously with capsules containing testosterone (T), estradiol (E2), dihydrotestosterone (DHT), E2 and DHT, or nothing (0). GDX females received E2, T, or empty (0) capsules immediately after surgery, and vehicle or progesterone (P4) injections at 4-day intervals. Basal nociception and morphine antinociception were tested 28 days after surgery on 50 degrees C and 54 degrees C hotplate tests, and reproductive behavior and physiology were assessed shortly thereafter. There were no significant differences in baseline hotplate latencies among the male treatment groups, but morphine was significantly more potent in sham and GDX+T males than in GDX+0 males. The ability of T to increase morphine's potency was approximated by its major metabolites E2 and DHT, given together but not alone. Baseline hotplate latencies were higher in sham females tested during diestrus than in those tested during estrus. Morphine was significantly more potent in sham females tested during proestrus and diestrus than in those tested during estrus. Baseline hotplate latencies were significantly higher, and morphine was significantly less potent in GDX+E2, GDX+E2/P4 and GDX+T females than in GDX+0 females. All group differences in basal nociception and morphine antinociception observed on the 50 degrees C hotplate test were smaller and generally non-significant on the 54 degrees C hotplate test. Steroid manipulations produced the expected changes in reproductive behaviors and steroid-sensitive organs. These results demonstrate that in adult rats, gonadal steroid manipulations, that are physiologically relevant, modulate (1) basal nociception in females but not males, and (2) morphine's antinociceptive potency in both males and females.

Cannabinoids are currently used for the treatment of excessive weight loss and nausea; however, there are very few studies that have examined cannabinoid effects in females of any species. A previous study has shown that there are sex differences in cannabinoid pharmacokinetics in rats, suggesting that there could be sex differences in cannabinoid-induced behaviors. To address this issue, Delta9-tetrahydrocannabinol, 11-hydroxy-Delta9-tetrahydrocannabinol (natural cannabinoids) or (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxypropyl)cyclohexanol) (CP55940, a synthetic cannabinoid) was administered i.p. to male and female Sprague-Dawley rats, who were tested on the 50 degrees C warm water tail withdrawal, paw pressure, catalepsy bar and spontaneous locomotor activity tests at various times post-injection. At the doses tested, all three cannabinoid agonists produced greater effects in females than males in two or more behavioral tests. This study demonstrates that there are sex differences in the behavioral effects of cannabinoids in the rat.

A number of investigators have shown that male animals are more sensitive than females to the antinociceptive effects of mu-opioid agonists. The present study was conducted to examine sex differences in opioid antinociception in the rat using agonists known to differ in selectivity for and efficacy at kappa- versus mu-receptors. Dose- and time-effect curves were obtained for s.c. U69593, U50488, ethylketazocine, (-)-bremazocine, (-)-pentazocine, butorphanol and nalbuphine on the 50 or 54 degrees C hotplate and warm water tail withdrawal assays; spontaneous locomotor activity was measured 32-52 min post-injection in the same rats. On the hotplate assay, only butorphanol (54 degrees C) and nalbuphine (50 degrees C) were significantly more potent in males than females. On the tail withdrawal assay, all agonists were significantly more potent or efficacious in males than females at one or both temperatures. In contrast, no agonist was consistently more potent in one sex or the other in decreasing locomotor activity. Estrous stage in female rats only slightly influenced opioid effects, accounting for an average of 2.6% of the variance in females' antinociceptive and locomotor responses to drug (50 degrees C experiment). These results suggest that (1) sex differences in antinociceptive effects of opioids are not mu-receptor-dependent, as they may occur with opioids known to have significant kappa-receptor-mediated activity; (2) the mechanisms underlying sex differences in kappa-opioid antinociception may be primarily spinal rather than supraspinal; (3) sex differences in antinociceptive effects of opioid agonists are not secondary to sex differences in their sedative effects.