Mitchell J. Picker

Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity, and efficacy at the µ opioid receptor

Abstract. Rationale: Recent studies indicate that morphine is more potent as an antinociceptive agent in male than female rodents and monkeys. Objectives: To evaluate the influence of sex, nociceptive stimulus intensity and an opioids relative efficacy on opioid-induced antinociception in rat strains (F344 and Lewis) that display differential sensitivity to morphine antinociception. Methods: Antinociceptive testing was conducted using a rat warm-water (50–56°C) tail-withdrawal procedure. Dose–response and time-course determinations were performed with various opioids. Results: Across the nociceptive stimulus intensities tested, the high-efficacy µ opioids morphine, etorphine, and levorphanol were equally effective in males and females, but on average 2.5-fold more potent in males. At moderate stimulus intensities, the low-efficacy µ opioid buprenorphine was approximately 0.4-fold more potent in males, and at higher stimulus intensities more potent and effective (greater maximal effect) in males. At low stimulus intensities, the low-efficacy µ opioid dezocine and the µ/κ opioid butorphanol were greater than 8.9-fold more potent in males, and at moderate stimulus intensities were more potent and effective in males. At a low stimulus intensity, the µ/κ opioid nalbuphine was more potent and effective in males. At stimulus intensities in which buprenorphine, dezocine, butorphanol, and nalbuphine produced maximal effects in males but not females, these opioids antagonized the effects of morphine in females. Genotype-related differences were noted as opioids were generally more potent in F344 than Lewis males, whereas no consistent differences were observed between F344 and Lewis females. Conclusions: That sex differences in the potency and effectiveness of opioids increased with decreases in the opioids relative efficacy and with increases in the nociceptive stimulus intensity suggests that the relative efficacy of µ opioids as antinociceptive agents is greater in male than female rats.

Pharmacogenetic analysis of sex differences in opioid antinociception in rats

&NA; Sex differences in opioid antinociception have been reported in rodents and monkeys, with opioids being more potent in males than females. In the present study, the influence of rat strain on sex differences in opioid antinociception was examined in a warm water tail‐withdrawal procedure. Antinociceptive tests were conducted with the high‐efficacy &mgr;‐opioid morphine, and the less efficacious opioids buprenorphine, butorphanol and nalbuphine. Baseline nociceptive latencies were consistently higher in males than their female counterparts. Sex differences in opioid antinociception were observed in all strains tested, with the opioids being more potent and/or effective in males. The magnitude of the sex differences was related to the relative efficacy of the opioid, with morphine, buprenorphine, butorphanol and nalbuphine being on average 2.2‐, 2.6‐, 15.9‐ and 11.9‐fold more potent in males. Sex differences also varied markedly across strains, with large differences consistently obtained in the F344 and F344‐Sasco strains, moderate differences in the ACI, DA, Lewis, Sprague Dawley, Wistar and Wistar–Kyoto strains, and small differences in the Long Evans–Blue Spruce, Long Evans, Brown Norway and Holtzman strains. When compared across strains, there was no relationship between sex differences in nociceptive sensitivity and opioid sensitivity. These findings provide strong support for the role of genetic factors in determining sex differences in opioid antinociception, and suggest that the use of low‐efficacy opioids, coupled with the use of rat strains that display small and large sex differences in opioid antinociception, may provide a sensitive tool to investigate the mechanisms underlying sex differences in opioid antinociception.

Sex-related differences in mechanical nociception and antinociception produced by μ- and κ-opioid receptor agonists in rats

Previous studies indicate that in antinociceptive procedures employing thermal, chemical and electrical stimuli, opioids are generally more potent in male than female rodents. The purpose of the present study was to examine nociception and opioid antinociception in male and female rats using a mechanical nociceptive stimulus. Results indicated that males had a higher threshold for nociception, and in tests in which a constant pressure was applied to the hindpaw, the paw withdrawal latencies were consistently longer in males. Opioids with activity at the μ receptor, including levorphanol, morphine, dezocine, buprenorphine, butorphanol and nalbuphine, were generally more potent and/or effective in males. In contrast, sex differences were not consistently observed with the κ-opioid receptor agonists spiradoline, (5,7,8b)-N-methyl-N[2-1(1-pyrrolidinyl),1-oxaspiro[4,5]dec-8-yl benzeneacetamide (U69,593), trans-(±)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50,488), enadoline, ethylketocyclazocine, and nalorphine. These findings suggest that males and females differ in their responsiveness to mechanical nociception and that sex differences in sensitivity to κ-, but not μ-, opioid receptor agonists are specific to certain nociceptive stimulus modalities.

Sex and rat strain determine sensitivity to κ opioid-induced antinociception

Abstract.Rationale: Recent studies indicate that sex and rodent strain are determinants of sensitivity to opioid-induced antinociception. Objectives: The present study examined the influence of sex and rat strain on κ opioid-induced antinociception using a series of κ opioids that vary in their relative effectiveness. Methods: In a warm-water (50, 52 and 55°C) tail-withdrawal procedure, the antinociceptive effects of κ opioids were determined in male and female rats of the F344, Lewis and Sprague-Dawley (SD) strains. Results: In both males and females of each strain, spiradoline produced high levels of antinociception across all nociceptive stimulus intensities, whereas U50,488 produced high levels only at the low and moderate nociceptive stimulus intensities. Sex differences in the potency and effectiveness of these κ opioids were relatively small and not consistently obtained. Enadoline, bremazocine and nalorphine were less effective than spiradoline in producing antinociception, and at low and moderate nociceptive stimulus intensities these opioids were both more potent and effective in F344 and SD males than their female counterparts. In contrast, in Lewis rats, only bremazocine was more potent and effective in males. In combination tests, bremazocine shifted the spiradoline dose-effect curve leftward and/or upward in males and rightward in females (i.e., antagonized spiradoline). In contrast, in both males and females enadoline shifted the spiradoline dose-effect curve leftward and/or upward. Conclusions: These data indicate that κ opioids were generally more potent and effective as antinociceptive agents in males than females. Similar to data obtained with µ opioids, the magnitude of these sex differences was generally larger with the less effective κ opioids and determined, in part, by rat strain and nociceptive stimulus intensity.

Influence of gonadectomy on the antinociceptive effects of opioids in male and female rats

HeadingAbstractRationale. Sex differences in the antinociceptive effects of opioids have been reported in a variety of nociceptive assays, and it has been postulated that these differences are mediated by gonadal hormones.Objectives. The present study examined the influence of gonadectomy on opioid antinociception in male and female rats.Methods. In a warm-water, tail-withdrawal procedure, the antinociceptive effects of the high-efficacy µ opioids etorphine and morphine; the low-efficacy µ opioids buprenorphine and dezocine; and the low-efficacy, mixed-action opioids butorphanol and nalbuphine were examined in intact and gonadectomized rats of the F344 and Sprague Dawley (SD) strains.Results. The opioids examined were generally more potent in producing an antinociceptive effect in intact males than intact females, with larger sex differences observed with the less-effective opioids. In F344 males, gonadectomy produced small decreases in the potency of etorphine and morphine, and large decreases in the potency of buprenorphine, dezocine, butorphanol, and nalbuphine. Similar effects were obtained in SD males, with gonadectomy decreasing the potency of each of the opioids tested. In F344 females, gonadectomy produced small increases in the potency of etorphine and large increases in the potency of buprenorphine, dezocine, butorphanol, and nalbuphine. A similar effect was obtained in SD females, as gonadectomy increased the potency of etorphine, morphine, and buprenorphine. In both sexes, gonadectomy had a greater effect in F344 than SD rats.Conclusions. These findings suggest that gonadectomy decreases opioid antinociception in male rats and increases opioid antinociception in female rats. Additionally, the influence of gonadectomy on opioid antinociception appears to be determined by the relative effectiveness of the opioid tested and the rodent strain used.

Kappa antagonist properties of buprenorphine in non-tolerant and morphine-tolerant rats

Buprenorphine was evaluated for its ability to act as a kappa opioid antagonist in rats responding under a fixed-ratio 30 schedule of food presentation both before and after the induction of morphine tolerance. Before the induction of morphine tolerance, both buprenorphine and the selective kappa agonist bremazocine decreased rates of responding in a dose-dependent manner, and buprenorphine (0.03 and 0.3 mg/kg) failed to antagonize bremazocines rate-decreasing effects. Following the induction of morphine tolerance, the bremazocine dose-effect curve was unaffected, but a profound cross-tolerance developed to buprenorphine. Furthermore, buprenorphine (0.03, 0.3 and 1.0 mg/kg) produced a dose-dependent antagonism of the rate-decreasing effects of bremazocine in the morphine-tolerant rats. These results support the hypothesis that buprenorphine has antagonist activity at kappa opioid receptors.

Interactions between mu and kappa opioid agonists in the rat drug discrimination procedure.

The present study was designed to explore the nature of the interaction between mu and kappa opioid agonists in the rat drug discrimination procedure. In rats trained to discriminate the kappa agonist U50,488 (5.6 mg/kg) from water, the other kappa agonist bremazocine substituted completely for the U50,488 training stimulus, and the additional kappa agonist tifluadom substituted in three of five of rats tested. In contrast, the mu agonists morphine, fentanyl, and buprenorphine produced primarily vehicle-appropriate responding. When morphine, fentanyl, and buprenorphine were combined with the training dose of U50,488, all three mu agonists reduced U50,488-appropriate responding. In rats trained to discriminate the mu agonist morphine (10.0 mg/kg) from saline, the other mu agonists morphine and buprenorphine all substituted in a dose-dependent manner for the morphine training stimulus, whereas U50,488, bremazocine, and tifluadom produced primarily vehicle-appropriate responding. When combined with the training dose of morphine, bremazocine antagonized morphines discriminative stimulus effects, whereas U50,488 and tifluadom had no effect. The barbiturate pentobarbital neither substituted for, nor antagonized, the discriminative stimulus effects of either U50,488 or morphine. These results suggest that mu agonists and kappa agonists produce interacting effects in the drug discrimination procedure in rats.

The Schism Between Experimental and Applied Behavior Analysis: Is It Real and Who Cares?

This paper addresses the relationship between the experimental analysis of behavior and applied behavior analysis. Citation data indicate that across time the Journal of the Experimental Analysis of Behavior, and other experimental sources, have been referenced increasingly infrequently in the Journal of Applied Behavior Analysis, Behavior Therapy, and Behavior Research and Therapy. Such sources are now rarely cited in these journals, and never have been regularly referenced in Behavior Modification. Although their proper interpretation is far from certain, these data partially support recent suggestions that the experimental analysis of behavior and applied behavior analysis are largely separate, insular fields. A questionnaire, mailed to the editorial staffs of the Journal of the Experimental Analysis of Behavior and the Journal of Applied Behavior Analysis, was intended to gather further information about the alleged schism between the fields. Few respondents regularly read both journals, publish in both journals, or find both journals useful in their current research efforts. The majority of editors of both journals indicated that the fields were growing apart, although there was no consensus that this is harmful for behavior analysis. Most editors of the Journal of Applied Behavior Analysis reported that research published in the Journal of the Experimental Analysis of Behavior has decreased in value to applied researchers across time; most editors of the Journal of the Experimental Analysis of Behavior indicated that research published there has not changed in applied value. Several respondents commented at length concerning the relationship of experimental and applied behavior analysis. These comments, many of which appear in the article, reveal a marked plurality of views.

Effect of strain and sex on μ opioid receptor-mediated G-protein activation in rat brain

Strain and sex differences in mu opioid-mediated antinociception have been reported in rodents. The present studies evaluated mu opioid receptor-mediated G-protein activation in Lewis and Fischer 344 (F344) male and female rats using agonist-stimulated [35S]GTPgammaS binding. Compared to Lewis rats, F344 rats exhibited a 35% higher level of net DAMGO-stimulated [35S]GTPgammaS binding in striatum. Basal [35S]GTPgammaS binding was approximately 30% lower in thalamus of Lewis than F344 rats. Female Lewis rats also exhibited slightly ( approximately 15%) lower basal [35S]GTPgammaS binding in cingulate cortex relative to F344 rats of either sex. The relative efficacies of the mu partial agonists, morphine and buprenorphine, were also examined. Buprenorphine exhibited approximately 40% lower relative efficacy in the periaqueductal gray in Lewis compared to F344 rats, but no other relative efficacy differences were found between strains or sexes. Moreover, regional differences in the relative efficacy of buprenorphine were also detected in Lewis but not F344 rats. In contrast to these results, the only difference found between sexes was the 13% lower basal [35S]GTPgammaS binding in the cingulate cortex of female compared to male Lewis rats. These results suggest that differences in mu opioid receptor-mediated G-protein activation may contribute to strain differences in opioid antinociception, whereas sex differences may result predominantly from other mechanisms.

Predictors of High Ethanol Consumption in RIIβ Knock-Out Mice: Assessment of Anxiety and Ethanol-Induced Sedation

BACKGROUND Genetic and pharmacological evidence suggests that the cyclic adenosine monophosphate-dependent protein kinase A pathway modulates neurobiological responses to ethanol. Mutant mice lacking the RIIbeta subunit of protein kinase A (RIIbeta(-/-)) are resistant to ethanol-induced sedation and drink significantly more ethanol than littermate wild-type mice (RIIbeta(+/+)). We determined whether high ethanol intake by the RIIbeta(-/-) mice on alternate genetic backgrounds is reliably predicted by high basal levels of anxiety or resistance to the sedative effects of ethanol. METHODS Two-bottle choice procedures and a battery of behavioral tests (elevated plus maze, open-field activity, and zero maze) were used to assess voluntary ethanol consumption and basal levels of anxiety in RIIbeta(-/-) and RIIbeta(+/+) mice on either a C57BL/6J or a 129/SvEv x C57BL/6J genetic background. Additionally, ethanol-induced sedation and blood ethanol levels were determined in RIIbeta(-/-) and RIIbeta(+/+) mice after intraperitoneal injection of ethanol (3.8 g/kg). RESULTS RIIbeta(-/-) mice on both genetic backgrounds consumed more ethanol and had a greater preference for ethanol relative to RIIbeta(+/+) mice. However, RIIbeta(-/-) mice showed reduced basal levels of anxiety when maintained on the C57BL/6J background but showed increased anxiety when maintained on the 129/SvEv x C57BL/6J background. Consistent with prior research, RIIbeta(-/-) mice were resistant to the sedative effects of ethanol, regardless of the genetic background. Finally, RIIbeta(-/-) and RIIbeta(+/+) mice showed similar blood ethanol levels. CONCLUSIONS These results indicate that high ethanol consumption is associated with resistance to the sedative effects of ethanol but that basal levels of anxiety, as well as ethanol metabolism, do not reliably predict high ethanol drinking by RIIbeta(-/-) mice.