Gonadal hormone modulation of ∆9-tetrahydrocannabinol-induced antinociception and metabolism in female versus male rats.

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.

Anabolic-androgenic steroid effects on nociception and morphine antinociception in male rats.

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 3h 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 hot plate 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.

Forced swim test behavior in postpartum rats.

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, 2.5mg/kg) but not sertraline (serotonin reuptake inhibitor, 10mg/kg) or desipramine (norepinephrine reuptake inhibitor, 10mg/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.

Oestradiol dampens reflex-related activity of on- and off-cells in the rostral ventromedial medulla of 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.

Agonist/antagonist properties of nalbuphine, butorphanol and (-)-pentazocine in male vs. female rats.

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.

Importance of sex and relative efficacy at the mu opioid receptor in the development of tolerance and cross-tolerance to the antinociceptive effects of opioids.

RATIONALE: Recent studies indicate that mu 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 mu 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 mu opioid receptor in females.

Sex differences in antinociceptive and motoric effects of cannabinoids.

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.

Effects of chronic morphine treatment on responding for intracranial stimulation in female versus male rats.

Morphine was administered to Sprague-Dawley rats twice daily at 0, 3, 10, and 20 mg/kg/ injection during Weeks 1, 2, 3, and 4, respectively; responding for medial forebrain bundle stimulation was assessed 1, 2, and 3 hr after morning injections in female versus male rats. There were no sex differences in responding under control conditions (Week 1). Morphine's effect on response rate depended on dose, time post-injection, stimulation frequency, and day of treatment. Significant sex differences in morphine's effects occurred at 10 mg/kg, which decreased responding more in males at 1 hr and increased responding more in females at 2 hr, at some frequencies and on some test days. Similar trends were observed at other frequencies, test days, and doses. Morphine's differential effect in males versus females in this procedure suggests that sex comparisons of opioid effects in many animal models may be influenced by sex differences in opioid effects on behavioral output.

Sex differences in opioid antinociception: kappa and 'mixed action' agonists.

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.

Receptor-selective antagonism of opioid antinociception in female versus male rats.

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.

Lotrafiban: an oral platelet glycoprotein IIb/IIIa blocker.

Platelets play a major role in thrombus formation, as well as in the pathogenesis of atherothrombosis. Inhibition of platelet function is now emphasised more than ever for prevention and treatment of almost all vascular diseases, since thrombosis is established as the key pathogenic event causing acute ischaemic coronary and cerebrovascular syndromes. Although acetylsalicylic acid (aspirin) has been shown to reduce the incidence of myocardial infarction and stroke, its effect is weak and more effective antithrombotic agents are required to manage patients at high-risk for recurrent vascular events. Platelet glycoprotein IIb/IIIa receptor (GPIIb/IIIa) blockade represents a significant advance in interventional cardiology and treatment of acute ischaemic syndromes. The past several years have seen the introduction of many platelet GPIIb/IIIa blockers into the clinical arena targeting the unique platelet GPIIb/IIIa receptor for the adhesive proteins, fibrinogen and von Willebrand Factor. Platelet GPIIb/IIIa blockers administered intravenously have proven efficacious in mitigating arterial thrombosis in acute coronary syndromes (unstable angina and non-ST-elevation myocardial infarction) and percutaneous coronary interventions (PCI) such as balloon dilatation and stent implantation. Currently, orally-active platelet GPIIb/IIIa blockers are being developed to provide additional benefits for primary and secondary prevention of thrombosis as chronic treatment, especially in high-risk patients. Lotrafiban (SmithKline Beecham) is a member of the latest generation of orally-active platelet GPIIb/IIIa blockers undergoing Phase III clinical trials to test the relative effectiveness versus other oral platelet inhibitors for ischaemic conditions including unstable angina, restenosis after PCI and stroke. Lotrafiban is converted from an esterified prodrug by plasma and liver esterases to a peptidomimetic of the arginine-glycine-aspartic acid amino acid sequence. This sequence itself mimics the binding site of fibrinogen and von Willebrand Factor to the platelet GPIIb/IIIa receptor. Preliminary results of the clinical trial APLAUD (antiplatelet useful dose) show that lotrafiban is clinically safe and well-tolerated in patients with recent myocardial infarction, unstable angina, transient ischaemic attack (TIA), or stroke when added to aspirin therapy. With lotrafiban, a worldwide large-scale Phase III clinical trial BRAVO (blockage of the GPIIb/IIIa receptor to avoid vascular occlusion) is currently underway. In general, GPIIb/IIIa blockade seems clinically very promising. A number of unresolved issues, however, remain to be elucidated.

Kappa opioid-induced diuresis in female vs. male rats.

Kappa opioid agonists may produce dissimilar discriminative and analgesic effects in female vs. male subjects. The present study was conducted to determine whether a prototypic physiological effect of kappa agonists--diuresis--also differs between the sexes. When data were not corrected for individual differences in body weight, the kappa agonists U69,593 (0.03-3.0 mg/kg), U50,488 (0.3-10 mg/kg), (-)-bremazocine (0.001-0.1 mg/kg) and (-)-pentazocine (1-10 mg/kg), as well as a nonopioid diuretic, furosemide (1-10 mg/kg) produced significantly greater diuresis in normally hydrated, age-matched males than females; however, there was no sex difference in the diuretic effect of butorphanol (0.3-3.0 mg/kg), or in the antidiuretic effect of the mu agonist morphine (1.0-5.6 mg/kg, in water-loaded rats). In contrast, when data were corrected for individual difference in body weight, U69,593, U50,488, (-)-bremazocine, (-)-pentazocine, and furosemide produced nearly equivalent diuresis/kg in females and males, whereas butorphanol produced slightly greater diuresis/kg, and morphine produced significantly less antidiuresis/kg, in females than males. U69,593-induced diuresis was highly similar in males and females of similar body weight (i.e., different ages). U69,593 effects were dose-dependently antagonized by the kappa antagonist nor-binaltorphimine in both sexes, indicating a common, kappa receptor-mediated mechanism of action. (-)-Bremazocine was slightly more potent in suppressing vasopressin in 24-h water-deprived males than females. These results suggest that the greater diuretic effects of kappa receptor-selective opioid agonists in male rats are primarily due to males' larger body size (greater body water) relative to age-matched females, but may also be attributed to slightly greater vasopressin suppression in males.

Sex differences in development of morphine tolerance and dependence in the rat.

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.

Effect of gonadectomy on discriminative stimulus effects of morphine in female versus male rats.

In a previous study, we found sex differences in the potency of morphine as a discriminative stimulus; the present study was designed to determine whether sex differences in gonadal hormones contribute to sex differences in morphine's discriminative effects. Adult female and male rats were gonadectomized (GNDZ) or sham-gonadectomized (SHAM), and then trained to discriminate 3.0 mg/kg morphine from saline. The ED50 for morphine discrimination was significantly lower in females than in males (0.66 +/- 0.12 vs. 1.25 +/- 0.16 mg/kg, respectively); ED50 values in GNDZ rats were slightly higher than in SHAM rats. The time course of morphine discrimination was not significantly different in females and males, whether GNDZ or not. The micro agonist fentanyl completely substituted for morphine in all rats, with no group differences in ED50 value. The micro agonists buprenorphine and nalbuphine substituted for morphine in nearly all females and in all SHAM males, but in only four of seven GNDZ males. The kappa agonist U69,593 did not substitute for morphine in rats of any group. Most opioid agonists were significantly more potent in decreasing response rate in males than females, and in GNDZ than SHAM rats; morphine and nalbuphine also increased response rate above control in some females. A pA2 analysis of naltrexone in combination with morphine suggested that there were no significant differences among groups in receptors at which morphine produced its discriminative stimulus effects. Although hormone replacement in GNDZ female rats at the end of the study reinstated estrous cycling, it did not substantially alter the ED50 for morphine discrimination. Thus, sex differences in potency of morphine as a discriminative stimulus may not be due to sex differences in gonadal hormone milieu. The possibility that sex differences in reinforcement frequency on morphine versus saline levers caused the sex differences in morphine discrimination is discussed.

Sex differences in discriminative stimulus and diuretic effects of the kappa opioid agonist U69,593 in the rat.

Female and male rats were trained to discriminate the kappa opioid agonist (5alpha,7alpha,8beta)-(-)-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 ED50 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 ED50 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 ED50. 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 [3H]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.

Sex differences in cocaine- and nicotine-induced antinociception in the rat.

Several recent reports describe sex differences in opioid antinociception. The present study examined sex differences in stimulant-induced antinociception. On the 50 degreesC hotplate test, cocaine (0.1-1.0 microgram i.c.v.) produced dose- and time-dependent increases in response latency in male but not female Sprague-Dawley rats. In contrast, nicotine (3-30 microgram i.c.v.) produced increases in hotplate latency in both sexes, but produced greater effects in females; nicotine also decreased spontaneous locomotor activity significantly more in females than in males. These sex differences probably are not due to differential pharmacokinetics, and underscore the importance of including female subjects in experimental drug research.

Microinjection of morphine into the rostral ventromedial medulla produces greater antinociception in male compared to female rats.

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.

Reinforcement frequency, but not gender, determines sensitivity to discriminative stimulus effects of morphine.

We demonstrated previously that several parameters of a morphine discrimination were significantly different in female versus male rats, using a fixed ratio (FR)-10 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 3.0 mg/kg morphine from saline using a variable interval (VI) 15-s/VI 15-s (Phase I), a VI 7.5-s/VI 15-s (Phase II), and a VI 15-s/VI 15-s (Phase III) 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 I to Phase II, and back to the right from Phase II to III, 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.

Sex differences in opioid antinociception.

Previous studies indicate that mu opioid agonists such as morphine may produce greater antinociception in male than in female rodents. The present study was designed to investigate the generality of this finding across dose, time and type of opioid agonist. In adult female and male Sprague-Dawley rats, time-effect curves were obtained for vehicle and three doses each of the mu agonists fentanyl and buprenorphine, the kappa agonists (5alpha,7alpha,8alpha)-(-)-N-methyl-[7-(1-pyrrolidinyl )-1-oxaspiro-(4,5)dec-8-yl]benzeneacetamide (U69,593) and bremazocine and the delta agonists [D-Pen2,D-Pen5]enkephalin (DPDPE) and deltorphin on the 52 degrees C hot-plate and tail-withdrawal (immersion) assays. There were sex differences in the antinociceptive effects of the two kappa agonists and the two delta agonists, but the differences were assay-, dose- and/or time-dependent. Peak effects of U69,593 on tail withdrawal and DPDPE on hot plate tended to occur earlier in females than in males, and bremazocine produced greater tail-withdrawal antinociception in females than in males, whereas the highest doses of the two delta opioids produced greater hot-plate antinociception in males than in females. These results contrast with several previous reports showing that male rodents are more sensitive than females to the antinociceptive effects of mu and kappa (but not delta) opioids. These discrepancies may be caused by the more comprehensive examination of sex differences across dose and time used in the present study; sex differences that are dose- or time-dependent may not be apparent if a single dose or time point is examined. In addition, repeated testing procedures used in the present study may produce different results than acute testing procedures would, if female and male rats develop opioid tolerance at different rates.

Intracranial self-stimulation in female and male rats: no sex differences using a rate-independent procedure.

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 microA vs. 110.8 +/- 4.0 microA, 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.