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The study objective was to determine whether burrowing behavior is useful as a functional index of pain in both male and female rats, and whether a 'no-training' protocol can be used to increase testing efficiency. Adult Sprague-Dawley rats were injected in one or both hindpaws with oil vehicle or complete Freund's adjuvant (CFA); starting the next day, the amount of gravel each rat burrowed out of a tube in 1 h was measured daily for ≤7 days. Without preliminary training on the burrowing procedure, CFA reliably suppressed burrowing for 2-3 days compared to controls, in both sexes. However, whereas unilateral CFA completely suppressed burrowing 1-day post-CFA in nearly all males, bilateral CFA was required to do so in females. When administered 30 min before testing, once daily for 5 days post-CFA, the nonsteroidal anti-inflammatory drug ketoprofen (0.01-3.2 mg/kg) and the opioid morphine (0.1-3.2 mg/kg) significantly increased CFA-suppressed burrowing, whereas the purported cannabinoid analgesic Δ9-tetrahydrocannabinol (0.01-2.0 mg/kg) did not. The benzodiazepine chlordiazepoxide (1.25-10 mg/kg), included as a 'true negative' control, also did not restore CFA-suppressed burrowing in either sex. However, in CFA-treated males only, chlordiazepoxide decreased burrowing, suggesting that anxiety may contribute to burrowing in males but not females that are in pain. Overall these results suggest that burrowing is a valid, functional index of inflammatory pain in both sexes, and training on the burrowing procedure is not necessary. However, females are more avid burrowers than males, which should be considered when both sexes are used in inflammatory pain testing.

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.

Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), 2 of the primary constituents of cannabis, are used by some individuals to self-treat chronic pain. It is unclear whether the pain-relieving effects of CBD alone and in combination with THC are consistent across genders and among types of pain. The present study compared the effects of CBD and THC given alone and in combination in male and female rats with Complete Freund's adjuvant-induced inflammatory pain. After induction of hindpaw inflammation, vehicle, CBD (0.05-2.5 mg/kg), THC (0.05-2.0 mg/kg), or a CBD:THC combination (3:1, 1:1, or 1:3 dose ratio) was administered i.p. twice daily for 3 days. Then on day 4, mechanical allodynia, thermal hyperalgesia, weight-bearing, and locomotor activity were assessed 0.5 to 4 hours after administration of the same dose combination. Hindpaw edema and open field (anxiety-like) behaviors were measured thereafter. THC alone was anti-allodynic and anti-hyperalgesic, and decreased paw thickness, locomotion, and open field behaviors. CBD alone was anti-allodynic and anti-hyperalgesic. When combined with THC, CBD tended to decrease THC effects on pain-related behaviors and exacerbate THC-induced anxiety-like behaviors, particularly in females. These results suggest that at the doses tested, CBD-THC combinations may be less beneficial than THC alone for the treatment of chronic inflammatory pain. PERSPECTIVE: The present study compared CBD and THC effects alone and in combination in male and female rats with persistent inflammatory pain. This study could help clinicians who prescribe cannabis-based medicines for inflammatory pain conditions determine which cannabis constituents may be most beneficial.

Cannabinoid receptors are a potential target for anti-inflammatory and pain therapeutics. There are two subtypes, CB1 and CB2, and Δ9-tetrahydrocannabinol activates both of them, providing an analgesic effect but also psychoactive side effects. The psychoactive side effects are considered to be caused by activation of CB1, but not CB2. ABK5 is a CB2 subtype selective agonist that has a very different structure from known cannabinoid receptor agonists. Here, we report anti-inflammatory effects of ABK5 using the T-cell line Jurkat cells, and antinociceptive effect in an inflammatory pain model in rats. Production of the cytokines IL-2 and TNF-α was measured in stimulated Jurkat cells and MOLT-4 cells, and CXCL12-mediated chemotaxis of Jurkat cells was evaluated by a transwell migration assay. Anti-inflammatory and antinociceptive effects of ABK5 were also evaluated in a hindpaw CFA model in rats. ABK5 significantly decreased production of IL-2 and TNF-α measured as both mRNA and protein levels, and reduced chemotaxis towards CXCL12. It also attenuated edema and increased mechanical threshold in the hindpaw of CFA-treated rats. These results suggest that ABK5 is a good lead compound for the development of potential anti-inflammatory and analgesic agents.

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.

Cannabinoid receptors are a potential target for anti-inflammatory and pain therapeutics. There are two subtypes, CB

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. The present study compared the development of tolerance to the antinociceptive effects of THC given alone versus combined with CBD, in rats. 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. 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. 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.

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.

Current anti-migraine treatments have limited efficacy and many side effects. Although anecdotal evidence suggests that marijuana is useful for migraine, this hypothesis has not been tested in a controlled experiment. Thus, the present study tested whether administration of ∆9-tetrahydrocannabinol (THC) produces anti-migraine effects in the female rat. Microinjection of the TRPA1 agonist allyl isothiocyanate (AITC) onto the dura mater produced migraine-like pain for 3h as measured by depression of home cage wheel running. Concurrent systemic administration of 0.32 but not 0.1mg/kg of THC prevented AITC-induced depression of wheel running. However, 0.32mg/kg was ineffective when administered 90min after AITC. Administration of a higher dose of THC (1.0mg/kg) depressed wheel running whether rats were injected with AITC or not. Administration of a CB1, but not a CB2, receptor antagonist attenuated the anti-migraine effect of THC. These data suggest that: 1) THC reduces migraine-like pain when administered at the right dose (0.32mg/kg) and time (immediately after AITC); 2) THC's anti-migraine effect is mediated by CB1 receptors; and 3) Wheel running is an effective method to assess migraine treatments because only treatments producing antinociception without disruptive side effects will restore normal activity. These findings support anecdotal evidence for the use of cannabinoids as a treatment for migraine in humans and implicate the CB1 receptor as a therapeutic target for migraine.

Recent policy changes have led to significant increases in the use of cannabis for both medical and recreational purposes. Although men are more likely to endorse past month cannabis use and are more frequently diagnosed with Cannabis Use Disorder relative to women, a growing proportion of medical cannabis users are reported to be women. The increased popularity of cannabis for medical purposes and the narrowing gap in prevalence of use between men and women raises questions regarding sex-dependent effects related to therapeutic efficacy and negative health effects of cannabis and cannabinoids. The objective of this review is to provide a translational perspective on the sex-dependent effects of cannabis and cannabinoids by synthesizing findings from preclinical and clinical studies focused on sex comparisons of their therapeutic potential and abuse liability, two specific areas that are of significant public health relevance. Hormonal and pharmacological mechanisms that may underlie sex differences in the effects of cannabis and cannabinoids are highlighted.

Background Women report greater sensitivity to the subjective effects of Δ 9 -tetrahydrocannabinol (THC). Similarly, female rodents tend to be more sensitive to some pharmacological effects of THC and synthetic cannabinoids. This study examined sex differences in discriminative stimulus and response rate effects of THC and synthetic cannabinoids in rats. Methods A 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. Results 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. Conclusions 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.

The gonadal hormones testosterone (T) in adult males and estradiol (E2) in adult females have been reported to modulate behavioral effects of ∆9-tetrahydrocannabinol (THC). This study determined whether activational effects of T and E2 are sex-specific, and whether hormones modulate production of the active metabolite 11-hydroxy-THC (11-OH-THC) and the inactive metabolite 11-nor-9-carboxy-THC (THC-COOH). Adult male and female rats were gonadectomized (GDX) and treated with nothing (0), T (10-mm Silastic capsule/100g body weight), or E2 (1-mm Silastic capsule/rat). Three weeks later, saline or the cytochrome P450 inhibitor proadifen (25mg/kg; to block THC metabolism and boost THC's effects) was injected i.p.; 1h later, vehicle or THC (3mg/kg females, 5mg/kg males) was injected i.p., and rats were tested for antinociceptive and motoric effects 15-240min post-injection. T did not consistently alter THC-induced antinociception in males, but decreased it in females (tail withdrawal test). Conversely, T decreased THC-induced catalepsy in males, but had no effect in females. E2 did not alter THC-induced antinociception in females, but enhanced it in males. The discrepant effects of T and E2 on males' and females' behavioral responses to THC suggests that sexual differentiation of THC sensitivity is not simply due to activational effects of hormones, but also occurs via organizational hormone or sex chromosome effects. Analysis of serum showed that proadifen increased THC levels, E2 increased 11-OH-THC in GDX males, and T decreased 11-OH-THC (and to a lesser extent, THC) in GDX females. Thus, hormone modulation of THC's behavioral effects is caused in part by hormone modulation of THC oxidation to its active metabolite. However, the fact that hormone modulation of metabolism did not alter THC sensitivity similarly on all behavioral measures within each sex suggests that other mechanisms also play a role in gonadal hormone modulation of THC sensitivity in adult rats.

Mentor availability helps reduce the barriers facing women, providing skills and confidence necessary to successfully navigate different career stages in academia, and especially in Science, Technology, Engineering, and Math (STEM) related areas. For example, mentoring was noted to increase women’s persistence in engineering, and presumably other STEM fields (Frehill et al., 2006). Washington State University (WSU) began an External Mentor Program under the National Science Foundation ADVANCE Institutional Transformation award, and because of its success, this program is now sustained internally. Results of the WSU External Mentor Program evaluation (N=40) indicate that participating women faculty in STEM disciplines endorsed high levels of overall satisfaction with the External Mentor Program, reported that their expectations were met, and expressed consensus regarding recommending participation to their colleagues. All but one participant generated external grant proposals after taking part in the External Mentor Program. In-depth follow-up interviews revealed additional benefits, principally falling within the following domains: validation, collaboration, access and networking, and a “trickle down” effect - benefits conferred to the students, and participants’ departments more broadly. We conclude that External Mentor programming has emerged as an important tool in the arsenal of institutional strategies aimed at enhancing retention and advancement of women faculty in STEM fields.

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.

Current anti-migraine treatments have limited efficacy and many side effects. Although anecdotal evidence suggests that marijuana is useful for migraine, this hypothesis has not been tested in a controlled experiment. Thus, the present study tested whether administration of Δ9-tetrahydrocannabinol (THC) produces anti-migraine effects in the female rat. Microinjection of the TRPA1 agonist allyl isothiocyanate (AITC) onto the dura mater produced migraine-like pain for 3 h as measured by depression of home cage wheel running. Concurrent systemic administration of 0.32 but not 0.1 mg/kg of THC prevented AITC-induced depression of wheel running. However, 0.32 mg/kg was ineffective when administered 90 min after AITC. Administration of a higher dose of THC (1.0 mg/kg) depressed wheel running whether rats were injected with AITC or not. Administration of a CB1, but not a CB2, receptor antagonist attenuated the anti-migraine effect of THC. These data suggest that: 1) THC reduces migraine-like pain when administered at the right dose (0.32 mg/kg) and time (immediately after AITC); 2) THC’s anti-migraine effect is mediated by CB1 receptors; and 3) Wheel running is an effective method to assess migraine treatments because only treatments producing antinociception without disruptive side effects will restore normal activity. These findings support anecdotal evidence for the use of cannabinoids as a treatment for migraine in humans and implicate the CB1 receptor as a therapeutic target for migraine.

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.

Coronary heart disease is the leading cause of mortality in adult women, and recent trends indicate that risk for women, particularly working mothers, has worsened during the last decade. The absence of a biological explanation for this gender discrepancy has led some to look to psychosocial risk factors. This literature review examines the effect of multiple roles on women’s cardiovascular health. Further, a conceptual model of heart disease risk is proposed, which introduces background stress, a chronic stress burden, as a potential pathway between multiple roles and heart disease. Trends in the literature largely support the proposed conceptual model. Multiple roles that often place conflicting demands on women may affect health outcomes through an increase in total background stress. jabr_ 4..22 Coronary heart disease (CHD), the most prevalent form of cardiovascular disease, is the leading cause of death and disability among women in developed and developing countries (American Heart Association, 2009). Traditionally considered a “man’s disease,” in the last three decades, more U.S. women than men have died of heart disease annually. Although women develop CHD later than men, once the disease manifests, women have no survival advantage over men. Moreover, women have higher mortality and morbidity rates than men following myocardial infarction (MI), a difference particularly evident in younger (

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.

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.

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.

The present study was conducted to determine whether the ovarian steroid oestradiol alters the activity of nociceptive modulatory neurons in the rostral ventromedial medulla (RVM). Adult female rats were ovariectomized and implanted s.c. with an oestradiol-filled or placebo capsule. Sixteen to 37 days later, rats were anaesthetised for single unit recording from RVM neurons. On-cells were characterised by a burst of activity, and off-cells by a pause in activity immediately preceding reflexive withdrawal of the tail from 51 and 54 degrees C water. Although on- and off-cells were evident in both oestradiol- and placebo-treated rats, the reflex-related on-cell burst and off-cell pause were dampened in oestradiol-treated rats. On-cells from oestradiol-treated rats had a mean activity burst of 9.1+/-2.2 Hz in the 2 s preceding the tail withdrawal reflex to 51 degrees C water, compared with 17.9+/-4.3 Hz for on-cells in placebo controls. Off-cell activity during the 2 s preceding tail withdrawal was 4.8+/-2.2 vs. 0.1+/-0.1 Hz in oestradiol vs. placebo-treated females, respectively. Similar changes in on- and off-cell activity occurred when the tail was placed in 54 degrees C water. The present data demonstrate that oestradiol constrains the magnitude of the shift in RVM on- and off-cell activity associated with nociceptive reflexes.

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.