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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.

Estrous cycle-related fluctuations in delta-9-tetrahydrocannabinol (THC)-induced antinociception have been observed in the rat. The aim of this study was to determine which major ovarian hormone modulates the antinociceptive effects of i.c.v. THC, and whether hormone modulation of THC's behavioral effects could be due to changes in brain cannabinoid receptors (CBr). Vehicle (oil) or hormones (estradiol or progesterone, or both) were administered to female rats on days 3 and 7 post-ovariectomy. On the morning or afternoon of day 8 or day 9, vehicle or THC (100 μg) was administered i.c.v. Paw pressure, tail withdrawal, locomotor activity and catalepsy tests were conducted over a 3-h period. Estradiol (with and without progesterone) enhanced THC-induced paw pressure antinociception only. Ovarian hormones time-dependently modulated CBr in brain structures that mediate antinociception and locomotor activity, but the changes observed in CBr did not parallel changes in behavior. However, the time course of CBr changes must be further elucidated to determine the functional relationship between receptor changes and antinociceptive sensitivity to THC.

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.

We examined sex differences in antinociceptive and anti-inflammatory effects of delta-9-tetrahydrocannabinol (THC) using the complete Freund’s adjuvant (CFA) model of inflammatory pain (hindpaw CFA...

Temporal factors affecting desensitization of bladder sensory afferents to the capsaicin-like irritant resiniferatoxin (RTX) were studied, to determine optimal treatment parameters for clinical application of such substances. Four days after implantation of a chronic cannula into the bladder dome, vehicle or RTX (0.1–10 nmol) was injected into the bladders of awake, freely moving rats four times at 60-min intervals for exposure durations of 5, 15, or 45 min, or at intervals of 15, 60, or 120 min (duration 5 min). The first RTX injection dose-dependently increased time spent engaged in abdominal licking. Regardless of exposure interval and duration, time spent licking increased to a lesser extent with each subsequent injection, indicating desensitization of sensory afferents. Magnitude and duration of desensitization were dose dependent for all exposure regimens, and there were few differences between groups. Desensitization at 24 h was also greater in rats exposed four times compared to rats exposed once. Following four exposures to RTX, nearly complete recovery occurred within 7–14 days, in a dose-dependent manner. Thus, magnitude and duration of desensitization to locally administered RTX depend primarily on dose and number of exposures to RTX; duration of exposure and interval between exposures within the ranges studied were less important determinants.

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.

This study was undertaken to determine whether depression-like behavior can be observed in gonadally intact females that have experienced normal pregnancy. When tested on the forced swim test (FST) on postpartum days 1-7, previously pregnant rats spent slightly more time immobile, significantly less time swimming and diving, and defecated more than virgin controls. Subchronic treatment with nomifensine (DA reuptake inhibitor, 2.5 mg/kg) but not sertraline (serotonin reuptake inhibitor, 10 mg/kg) or desipramine (norepinephrine reuptake inhibitor, 10 mg/kg) significantly decreased immobility on postpartum day 2. In rats pre-exposed to the FST in mid-pregnancy, neither subchronic nor chronic treatment with desipramine or sertraline decreased immobility on postpartum day 2; in contrast, chronic desipramine significantly decreased immobility in virgin controls. These results indicate that postpartum female rats, compared to virgin controls, show a reduction in some “active coping behaviors” but no significant increase in immobility when tested during the early postpartum period, unlike ovariectomized females that have undergone hormone-simulated pregnancy (HSP). Additionally, immobility that is increased by FST pre-exposure is not readily prevented by treatment with standard antidepressant medications in postpartum females. Depression-like behaviors previously observed in females that have undergone HSP may result from the more dramatic changes in estradiol, prolactin or corticosterone that occur during the early “postpartum” period, compared to the more subtle changes in these hormones that occur in actual postpartum females.

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.

This study investigated estradiol (E(2)) modulation of the antidepressant effects of a selective serotonin (5-HT) reuptake inhibitor (SSRI; sertraline) and a tricyclic antidepressant (imipramine) as measured by the forced swim test (FST) followed by assessment of gene and protein expression for the 5-HT transporter (SERT) and multiple 5-HT receptors. Female Sprague-Dawley rats were ovariectomized (OVX) and two-thirds of the rats received E(2) implants (OVE). 4 weeks later, implants were withdrawn in half of the OVE rats (OVW) to capture a time point when E(2) levels were rapidly declining. Rats in each hormone group were treated with vehicle, sertraline (10 mg/kg) or imipramine (10 mg/kg), 24, 5 and 1h before the FST. Immediately after the FST, midbrain, hippocampus and prefrontal cortex tissue was removed and frozen for analysis of gene expression via quantitative real-time PCR (midbrain tissue) and protein expression via Western blot (prefrontal cortex and hippocampal tissue). In the FST, sertraline decreased immobility and increased swimming in OVE rats, as well as increased swimming in OVW rats. In contrast, no sertraline effect was observed in OVX rats. Rats treated with imipramine showed increased climbing but no changes in immobility or swimming. No changes in protein expression were detected in any treatment group. However, in vehicle-treated rats, E(2) increased midbrain SERT mRNA expression, with no effect on midbrain mRNA for the 5-HT receptors. In sertraline-treated rats, E(2) decreased 5-HT(2A) receptor mRNA, and E(2)-withdrawal increased 5-HT(1A), 5-HT(2A) and 5-HT(2C) receptor mRNA. In imipramine-treated rats, E(2) (and E(2)-withdrawal) did not affect mRNA expression for any of the target genes. Thus, E(2) synergized behaviorally and neurochemically with an SSRI but not a tricyclic antidepressant.

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)

It has become increasingly apparent that women suffer a disproportionate amount of pain during their lifetime compared to men. Over the past 15 years, a growing number of studies have suggested a variety of causes for this sex difference, from cellular to psychosocial levels of analysis. From a biological perspective, sexual differentiation of pain appears to occur similarly to sexual differentiation of other phenomena: it results in large part from organizational and activational effects of gonadal steroid hormones. The focus of this review is the activational effects of a single group of ovarian hormones, the estrogens, on pain in humans and animals. The effects of estrogens (estradiol being the most commonly examined) on experimentally induced acute pain vs. clinical pain are summarized. For clinical pain, the review is limited to a few syndromes for which there is considerable evidence for estrogenic involvement: migraine, temporomandibular disorder (TMD) and arthritis. Because estrogens can modulate the function of the nervous, immune, skeletal, and cardiovascular systems, estrogenic modulation of pain is an exceedingly complex, multi-faceted phenomenon, with estrogens producing both pro- and antinociceptive effects that depend on the extent to which each of these systems of the body is involved in a particular type of pain. Forging a more complete understanding of the myriad ways that estrogens can ameliorate vs. facilitate pain will enable us to better prevent and treat pain in both women and men.

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.

s / Drug and Alcohol Dependence 146 (2015) e118–e201 e195 Trends in racial/ethnic differences in heroin use and heroin risk behaviors among nonmedical users of prescription opioids from 2002 to 2011 Silvia S. Martins1, Julian Santaella1, Brandon D. Marshall 2, Adriana Maldonado1, Magdalena Cerda1 1 Epidemiology, Columbia University, New York, NY, United States 2 Epidemiology, Brown University, Providence, RI

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.

In september 2006 kwamen de leden van de belangengroepering (SIG) sekse- en genderspecifieke pijn van de International Association for the Study of Pain (IASP, de internationele associatie voor pijnonderzoek) bijeen om over de volgende onderwerpen te discussieren: 1) Wat is er bekend over sekse- en genderverschillen op het gebied van pijn en analgesie; en 2) Wat zijn de ‘best practice’-richtlijnen voor sekse- en genderspecifiek pijnonderzoek? Dit verslag is de consensus van deze bijeenkomst en omvat bijdragen uit algemeen wetenschappelijke hoek, van onderzoekers op het gebied van klinische en psychosociale pijn en van erkende deskundigen op het gebied van seksuele differentiatie en reproductieve endocrinologie.

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.

Rationale: Recent studies indicate that µ opioids are generally more potent and effective as antinociceptive agents in male than female rodents. Objectives: To evaluate the influence of sex on the development of tolerance to the antinociceptive effects of morphine and cross-tolerance to the lower efficacy µ opioids buprenorphine and dezocine in F344 and Lewis rats. Methods: Using a warm-water tail-withdrawal procedure, the antinociceptive effects of morphine, buprenorphine and dezocine were determined before and during chronic morphine (5, 10 and 20 mg/kg, b.i.d., for 7 and 14 days) administration. Results: Under acute conditions, morphine was more potent in males and during chronic morphine administration tolerance development was generally greater in males. As males were more sensitive to the acute effects of morphine, the functional chronic morphine dose (i.e., chronic morphine dose/acute morphine ED50) administered to males was larger than in females. Analyses of the relationship between the functional chronic morphine dose and tolerance indicated that morphine tolerance development was comparable in males and females. Under acute conditions, buprenorphine and dezocine were more potent and effective in males. During chronic morphine administration, cross-tolerance was conferred to these opioids as evidenced by rightward, and in some cases downward, shifts in their dose-effect curves. Decreases in the maximal effects produced by buprenorphine and dezocine were more frequently observed in females. Conclusions: That comparable levels of morphine tolerance were obtained in males and females when the functional chronic morphine dose was taken into consideration suggests that the mechanism underlying tolerance is not sex-dependent. Sex differences in the effectiveness of buprenorphine and dezocine when administered acutely and during chronic morphine administration further suggest that these opioids have lower efficacy at the µ opioid receptor in females.

Female and male rats were trained to discriminate the κ opioid agonist (5α,7α,8β)-(−)- N -methyl-[7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl]benzeneacetamide (U69,593, 0.13 mg/kg SC) from vehicle using a FR-10 schedule of food reinforcement. Female rats took significantly longer than males to acquire the discrimination (66.9 vs. 44.1 sessions, respectively), and the ED 50 for U69,593 discrimination was significantly higher in females than in males (0.074 vs. 0.025 mg/kg). The time course of U69,593 discrimination also differed between the sexes: peak and offset occurred earlier in females than in males. The ED 50 for bremazocine substitution was significantly higher in females than in males (0.0039 vs. 0.0006 mg/kg), whereas ethylketazocine substituted for U69,593 in all males and five of seven females, with no sex difference in substitution ED 50 . Morphine and BW373U86 did not substitute for U69,593 in a majority of rats of either sex. U69,593 also produced significantly less urine output/dose in females compared to males (e.g., 5.92 vs. 14.83 ml urine/kg body weight after 1.0 mg/kg U69,593), but was equipotent between the sexes in producing hot-plate antinociception. There was no sex difference in response rate-decreasing effect of any opioid agonist tested, and no sex difference in brain/blood ratio of [ 3 H]U69,593 measured in a separate group of rats, suggesting that sex differences observed in some effects of U69,593 probably are not due to sex differences in U69,593 pharmacokinetics. When retested at the end of the study, U69,593 and bremazocine were no longer differentially potent as discriminative stimuli in females and males, suggesting that factors that change over time (e.g., additional training, age, hormonal status) may contribute to initial sex differences in discriminability of U69,593.

Given gender differences in human drug use and dependence, this study examined sex differences in reinforcement processes that may underlie such behavior. A psychophysical determination of reinforcement threshold was made using an intracranial self-stimulation (ICSS) paradigm, electrically activating the medial forebrain bundle (MFB) as it passes through the lateral hypothalamus (LH). Using this response rate-independent procedure, basal reinforcement thresholds were not significantly different in male vs. female rats (119.4±3.3 μ A vs. 110.8±4.0 μ A, respectively; N =8/sex). Further, baseline reinforcement threshold did not fluctuate systematically across stages of the estrous cycle in female rats. The psychostimulants d -amphetamine (0.056–0.56 mg/kg s.c.) and cocaine (1.8–18.0 mg/kg i.p.) dose-dependently lowered reinforcement threshold, with no significant sex difference. The opioid morphine (0.56–5.6 mg/kg s.c.) did not significantly lower reinforcement threshold in either sex. These results contrast those of some previous studies that have used response rate-dependent measures of reinforcement threshold; procedures which are less rate-dependent may be more appropriate when examining subject variables such as sex and stage of estrous.

Eight female and 8 male rats were trained to discriminate 5.6 mg/kg i.p. cocaine from saline on 2-lever, food-reinforced drug discrimination procedure. Female rats acquired the cocaine discrimination in approximately the same number of sessions that males did (43 +/- 7 vs. 51 +/- 9 sessions, respectively), and the ED50 for cocaine discrimination was nearly equivalent in female and male rats (2.46 +/- 0.41 vs. 2.32 +/- 0.49 mg/kg, respectively). The time course for cocaine discrimination was similar in female and male rats, except the offset of cocaine's effects occurred significantly earlier in females than in males. D-Amphetamine dose-dependently substituted for cocaine in all 7 males and 6 of 7 females tested, with no significant sex difference in the ED50 values for D-amphetamine substitution. None of the three opioid agonists tested, morphine (mu), U69,593 (kappa) or BW373U86 (delta), fully substituted for cocaine in rats of either sex. The dopamine antagonist fluphenazine blocked the discriminative stimulus effects of cocaine to approximately the same extent in both sexes. Further drug discrimination training with a higher dose of cocaine, 10 mg/kg, did not significantly alter the ED50 for cocaine discrimination, and there was still no significant sex difference in ED50 values (3.50 +/- 0.39 vs. 2.36 +/- 0.41 mg/kg in females vs. males, respectively). In these same rats, however, cocaine (1-10 mg/kg) produced significantly greater locomotor activation in females than in males on a test of spontaneous locomotor activity. Thus, these results suggest that there are few sex differences in discriminative stimulus effects of cocaine, even at doses that produce significantly different locomotor responses in female versus male rats.

The irritancy of initial application of capsaicin and related substances limits their therapeutic potential as novel analgesics. The purpose of the present study was to determine whether the irritant properties of the potent, capsaicin-like compound resiniferatoxin (RTX) would be attenuated by pretreatment with a local anesthetic and to determine whether the local anesthetic had significant effects on RTX-induced desensitization of sensory afferents. A model of visceral nociception in which irritants are instilled directly into the bladder (intravesical, i.ves.) of awake, freely moving rats was used. The nociceptive response, abdominal licking (grooming) was scored for 15 min; locomotor activity was scored concurrently. Tetracaine (0.125-1.0%) attenuated the increases in abdominal licking produced by RTX (3.0 nmol) in a dose- and time-dependent manner. At high doses, tetracaine also suppressed locomotor activity. Thirty minutes and 24 h later, the same dose of RTX was administered again to assess development of desensitization of bladder sensory afferents. Rats that had been pretreated with saline showed decreases in licking behavior from the first to subsequent injections of RTX, indicating the development of desensitization. Tetracaine-pretreated rats showed equivalent or significantly greater decreases in licking behavior, suggesting that local anesthetic pretreatment either did not alter or enhanced development of desensitization to RTX. In a second experiment, tetracaine (0.25 or 0.5%) produced similar effects against a high dose of RTX (3.0 nmol), but did not consistently alter excitatory or desensitizing effects of a low dose of RTX (0.1 nmol).(ABSTRACT TRUNCATED AT 250 WORDS)

This study characterized the excitatory (nociceptive) and desensitizing (antinociceptive) properties of the natural pungent substances, capsaicin (CAP) and resiniferatoxin (RTX) instilled in the bladder (intravesical, i.ves.) via an indwelling cannula in awake, freely moving rats. The incidence of 9 behaviors was scored for 10 min following i.ves. vehicle or RTX (1.0 nmol). Abdominal licking and head-turning occurred significantly more often in RTX-treated rats compared to vehicle controls, whereas head-grooming, locomotion, rearing and biting did not differ between the two groups. Little or no vocalization, defecation or hindlimb hyperextension was observed in either RTX- or vehicle-treated rats. A second injection of either vehicle or RTX administered to RTX-treated rats 60 min later did not significantly increase abdominal licking or head-turning compared to vehicle controls; this subsequent lack of excitation was taken as a measure of desensitization. In a separate experiment, the first injection of i.ves. RTX (0.1–3.0 nmol) increased licking in a dose-dependent manner; in contrast, the first injection of i.ves. CAP (0.1–3.0 μmol) significantly increased licking only at the intermediate dose tested, 1.0 μmol. With each subsequent injection of the same drug and dose at 30-min intervals, licking increased to a lesser extent, such that it was not significantly different from control after the fourth injection. Rats treated with i.ves. CAP or RTX also did not show increased licking when administered the opposite treatment 30 min later (RTX or CAP, respectively), indicating cross-desensitization; however, i.ves. administration of a third, higher dose of RTX reinstated licking behavior in these ‘desensitized’ rats. Subcutaneous administration of CAP (18–180 mg/kg) or RTX (18–180 μg/kg) dose-dependently attenuated the excitatory response to i.ves. CAP and RTX administered 2 days later. Whereas rats treated systemically with RTX also were desensitized to the excitatory effects of RTX instilled in the eye (evaluated in the eye-wipe assay), rats treated i.ves. with RTX and vehicle-treated rats showed a normal eye-wiping response. Finally, pretreatment with i.ves. ruthenium red, a cation channel blocker, antagonized the excitatory and desensitizing effects of i.ves. RTX. This study demonstrates that repeated application of both CAP and RTX into the bladder produces behavioral effects indicative of local sensory afferent desensitization. I.ves . CAP and RTX appear to produce their excitatory and desensitizing effects via a common mechanism, which is dependent on cation channel activation. Furthermore, desensitization via i.ves. RTX administration appears to be specific to bladder afferents, occurs at low doses, and can be achieved over a broad dose range with minimal disruption of other behaviors. This study demonstrates for the first time that desensitization of sensory afferents in a deep structure can be produced via local application of RTX in awake, freely moving animals. Insofar as CAP-sensitive innervation regulates both pain and micturition in the human bladder, the i.ves. model in rats may be useful in assessing the utility of local afferent desensitization for the treatment of neuropathic bladder disorders.

Desensitization of sensory afferents with topical capsaicin has been employed to treat a variety of neuropathic disorders in humans, however, few studies have been undertaken to systematically evaluate treatment parameters to determine the optimal dose and frequency of treatment needed to achieve and maintain desensitization. The effects of several treatment parameters, including dose, number of exposures, interval between exposures and duration of exposure, on the development, magnitude and duration of desensitization following local treatment with capsaicin and related compounds are described.

We demonstrated previously that several parameters of a morphine discrimination were significantly different in female versus male rats, using a fixed ratio (FR)-l0 schedule of food reinforcement however, this schedule produced a significant bias in reinforcement frequency between saline and morphine sessions in males but not in females. To determine whether this schedule—drug—sex interaction caused the sex difference in discriminability of morphine, female and male rats were trained to discriminate 3.0mg/kg morphine from saline using a variable interval (VI) 15-s/VI 15-s (Phase 1), a VI 7.5-s/Vl 15-s (Phase II), and a VI 15-s/Vl 15-s (Phase 111) schedule of food reinforcement on morphine/saline levers, respectively. After a minimum of 40 training sessions in each phase, mean reinforcement rates in morphine sessions were highest and the ED50 values for morphine discrimination were lowest, in Phase II. Thus, as predicted, the morphine dose-effect curves shifted to the left from Phase 1 to Phase II, and back to the right from Phase n to m, presumably due to the bias in reinforcement rate between saline and morphine sessions that was induced by manipulating the VI schedule on the morphine lever. However, there were no sex differences in the morphine versus saline reinforcement rate or in discrimination ED50 in any phase, suggesting that the sex difference observed in our initial study was probably due to the bias in reinforcement frequency (towards the saline condition) that occurred only in males under the FR-10 schedule. This study demonstrates the importance of considering group differences in schedule—drug interactions when comparing discriminative stimulus properties of drugs between groups. Behav Pharmacol 1998; 9:357–362 1998 Lippincott-Raven Publishers.

Rats exposed to a presumably aversive stimulus such as electric shock respond by heaping litter on the source, a behavior known as conditioned defensive burying (CDB). Because some anxiolytics suppress this behavior, CDB has been proposed as a screening method for anxiolytics. We tested the effects of the conventional anxiolytics chlordiazepoxide (4-32 mg/kg) and meprobamate (75-125 mg/kg), the novel anxiolytic buspirone (8-64 mg/kg), the antidepressant imipramine (4-16 mg/kg), the opiate analgesic morphine (2-8 mg/kg), and the antipsychotic chlorpromazine (1-16 mg/kg) on CDB. Chlordiazepoxide, meprobamate, imipramine, and morphine significantly suppressed CDB, but chlordiazepoxide did so only at a dose that reduced general activity. Buspirone and chlorpromazine did not suppress CDB at doses that reduced activity. There were some methodological differences from previous studies. We conclude that the test as constituted in this study lacks drug-class specificity. The necessity of distinguishing between specific reduction of burying and general reduction of activity is emphasized.

In a standard two-lever drug discrimination paradigm, rats were trained to discriminate nicotine 0.5 mg/kg PO from saline. Injections occurred 15 min before the session. Subjects reached the training criterion in a mean of 38 sessions. Nicotine PO, SC, and IP generated similar dose-effect curves (ED50 = 0.073 mg/kg PO, 0.076 mg/kg SC, 0.090 mg/kg IP); the dose-effect curve for transdermal (TD) administration fell approximately 1 log unit to the right (ED50 = 1.34 mg/kg). The percentage of rats choosing the nicotine-appropriate lever peaked at 15 min and gradually decreased to 50% or less by 180 min for nicotine PO and TD, a time-decay function similar to that previously shown for SC administration. The nicotinic cholinergic agonist cytisine (0.5-8.0 mg/kg) PO and TD produced up to 56% nicotine-appropriate responding, while the muscarinic cholinergic agonist arecoline (1.0-4.0 mg/kg) PO and TD produced only saline-appropriate responding. The nicotine cue did not generalize to the cholinergic antagonist mecamylamine (0.125-0.5 mg/kg) PO or TD; mecamylamine 0.5 mg/kg PO but not TD completely blocked the PO and TD nicotine cues. These results show that an approximately equal cue occurs with PO, IP, and SC administration, and that the TD cue is considerably weaker. The significance of the procedure as an animal analog of human transdermal nicotine intake is discussed.