RESUMEN
In acute pain models, N-methyl-D-aspartate (NMDA) antagonists enhance the antinociceptive effects of morphine to a greater extent in males than females. The purpose of this investigation was to extend these findings to a persistent pain model which could be distinguished from acute pain models on the basis of the nociceptive fibers activated, neurochemical substrates, and duration of the nociceptive stimulus. To this end, persistent hyperalgesia was induced by administration of capsaicin in the tail of gonadally intact F344 rats, following which the tail was immersed in a mildly noxious thermal stimulus, and tail-withdrawal latencies measured. For comparison, tests were conducted in two acute pain models, the hotplate and warm water tail-withdrawal procedures. In males, the non-competitive NMDA antagonist dextromethorphan enhanced the antihyperalgesic effect of low to moderate doses of morphine in a dose-and time-dependent manner. Across the doses and pretreatment times examined, enhancement was not observed in females. Enhancement of morphine antinociception by dextromethorphan was seen in both males and females in the acute pain models, with the magnitude of this effect being greater in males. These findings demonstrate a sexually-dimorphic interaction between NMDA antagonists and morphine in a persistent pain model that can be distinguished from those observed in acute pain models.
Asunto(s)
Analgésicos Opioides/farmacología , Capsaicina , Antagonistas de Aminoácidos Excitadores/farmacología , Hiperalgesia/tratamiento farmacológico , Morfina/farmacología , N-Metilaspartato/antagonistas & inhibidores , Enfermedad Aguda , Animales , Interpretación Estadística de Datos , Dextrometorfano/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Calor , Hiperalgesia/inducido químicamente , Masculino , Dimensión del Dolor/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Caracteres SexualesRESUMEN
RATIONALE: Sex differences in the potency of the antinociceptive effects of kappa opioids have been reported in various acute pain models with evidence suggesting that these sex differences are mediated by activity in the N-methyl-D: -aspartate (NMDA) system. OBJECTIVES: The purpose of the present study was to evaluate sex differences in the antihyperalgesic actions of selected kappa and mixed-action opioids in a persistent pain model and determine if the NMDA system modulates these effects in a sexually dimorphic manner. METHODS: Using gonadally intact male and female F344 rats, hyperalgesia was induced by local administration of capsaicin in the tail, after which the tail was immersed in a mildly noxious thermal stimulus (45 degrees C water), and tail-withdrawal latency measured. Opioids were then administered systemically (s.c.) and locally (in the tail) alone, and in selected combinations with the noncompetitive NMDA antagonist dextromethorphan. RESULTS: When administered systemically and locally, the kappa opioids spiradoline, U69,593 and U50,488, and the mixed-action opioids butorphanol and nalbuphine, produced dose-dependent antihyperalgesic effects. Whereas the kappa opioids were generally more potent in males, sex differences were not observed with the mixed-action opioids. Peripheral receptor activity was confirmed for local administration of kappa opioids by the antagonism observed after local, but not intracerebroventricular (i.c.v.), administration of the kappa antagonist nor-binaltorphamine (nor-BNI). Dextromethorphan was equally potent in attenuating the antihyperalgesia induced by kappa opioids in both males and females. CONCLUSIONS: These findings demonstrate sex differences in kappa opioid activity in a persistent pain model. Although an NMDA antagonist blocked the effects of kappa opioids in this model, these effects were not sexually dimorphic as reported in most acute pain models.
Asunto(s)
Analgésicos Opioides/farmacología , Hiperalgesia/tratamiento farmacológico , Inflamación/tratamiento farmacológico , N-Metilaspartato/fisiología , Dolor/tratamiento farmacológico , Análisis de Varianza , Animales , Capsaicina , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Hiperalgesia/inducido químicamente , Inflamación/inducido químicamente , Inyecciones Intraventriculares , Inyecciones Subcutáneas , Masculino , Dolor/inducido químicamente , Dimensión del Dolor , Ratas , Ratas Endogámicas F344 , Receptores Opioides/metabolismo , Factores SexualesRESUMEN
In a recently proposed bimodal opioid receptor model, the inhibitory actions of opioids on action potential duration in dorsal root ganglion neurons have been proposed to produce antinociception, and the excitatory actions of hyperalgesia. Recent studies indicate that selectively blocking these excitatory actions with low doses of opioid antagonists enhances opioid antinociception and attenuates the development of opioid tolerance. To determine if the excitatory actions of opioids contribute to sex as well as strain differences in opioid sensitivity, the effects of morphine alone and in combination with low doses of naltrexone were examined in male and female rats of four strains. The strains examined differed in their sensitivity to opioid antinociception and magnitude of sex differences in opioid sensitivity. All testing was conducted using a thermal tail-flick procedure with the nociceptive stimulus intensity adjusted so that baseline latencies were comparable across strains/sexes. In chronic studies, the morphine dosing regimen was adjusted in each strain/sex to produce comparable levels of tolerance. In each of the strains tested, morphine produced dose-dependent increases in antinociception, with differences in morphine potency observed across strains and sexes. In male and female Sprague-Dawley and Long-Evans rats, naltrexone enhanced morphine antinociception and attenuated the development of morphine tolerance. These effects were not observed in F344 and Lewis rats, even when tests were conducted across a range of morphine and naltrexone doses. These results suggest that the ability of low doses of naltrexone to enhance opioid antinociception does not contribute to sex or rat strain differences in opioid sensitivity.
Asunto(s)
Modelos Animales de Enfermedad , Morfina/administración & dosificación , Naltrexona/administración & dosificación , Umbral del Dolor/efectos de los fármacos , Dolor/prevención & control , Dolor/fisiopatología , Analgésicos , Analgésicos Opioides/administración & dosificación , Animales , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Sinergismo Farmacológico , Tolerancia a Medicamentos , Femenino , Masculino , Antagonistas de Narcóticos/administración & dosificación , Ratas , Ratas Endogámicas F344 , Ratas Long-Evans , Ratas Sprague-Dawley , Factores Sexuales , Especificidad de la EspecieRESUMEN
Researchers have recently become aware of the importance of including women in research, including drug abuse research. With this increased awareness has come an increased scientific interest in the potential influence of menstrual cycle phase on responses to drugs. In this review, we discuss recent studies that have examined subjective and physiological responses to drugs of abuse in relation to menstrual cycle phase. With most of the drugs reviewed, including alcohol, benzodiazepines, caffeine, marijuana, nicotine and opioids, responses to the drugs were not different were inconsistent across cycle phases. However, with psychomotor stimulant drugs, such as amphetamine and cocaine, responses to the drugs were greater during the follicular, compared to the luteal, phase of the cycle. These findings suggest that, consistent with certain pre-clinical findings, circulating levels of ovarian hormones influence the central effects of stimulant drugs in women. With other drugs, the evidence to date suggests that ovarian hormones have modest, if any, effects on responses to abused drugs. We discuss methodological issues relating to inclusion of women with regular menstrual cycles.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Ciclo Menstrual/efectos de los fármacos , Trastornos Relacionados con Sustancias/epidemiología , Femenino , HumanosRESUMEN
Although studies suggest that 2-(3,4-dichlorophenyl-N-methyl-N-[(1S)-1-(3-isothiocyanatophenyl)-2-(1-pyrrolidinyl) ethyl] acetamide (DIPPA) has transient kappa-opioid-mediated agonist effects followed by long-lasting kappa-antagonist effects, its behavioral and pharmacological actions have not been systematically examined and there is evidence suggesting that some of its effects are species dependent. The purpose of this investigation was to examine the actions of DIPPA in different behavioral procedures and in three species. In a pigeon drug discrimination procedure, DIPPA and the kappa-opioids U50,488 and ICI-199441 substituted fully for the stimulus effects produced by spiradoline. For DIPPA, this effect was observed between 0.25 and 4 h after administration. In a warm water tail-withdrawal procedure, DIPPA failed to produce antinociception in rats or mice even when relatively high doses were tested using pretreatment intervals ranging from 0.25 to 24 h. In this procedure, DIPPA antagonized the effects of spiradoline and U50,488 in mice. In rats, DIPPA antagonized the effects of U50,488 but not those of spiradoline. Taken together, these results suggest that DIPPA may function as a low-efficacy kappa-opioid and have a long duration of action, and there may be some species differences in its behavioral profile. This profile of action, however, differs from other low-efficacy kappa-opioids.
Asunto(s)
Acetamidas/farmacología , Isotiocianatos/farmacología , Receptores Opioides kappa/agonistas , 3,4-Dicloro-N-metil-N-(2-(1-pirrolidinil)-ciclohexil)-bencenacetamida, (trans)-Isómero/farmacología , Analgésicos/farmacología , Analgésicos no Narcóticos/farmacología , Animales , Columbidae , Condicionamiento Operante/efectos de los fármacos , Dextroanfetamina/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Ratones , Narcóticos/farmacología , Dimensión del Dolor/efectos de los fármacos , Pirrolidinas/farmacología , Ratas , Ratas Long-Evans , Tiempo de Reacción/efectos de los fármacosRESUMEN
UNLABELLED: Evidence suggests that gonadal hormones can modulate sensitivity to nociceptive stimuli and opioid antinociception. However, cross-study comparisons addressing the nature of this modulation have been complicated by a number of methodologic factors, including the use of different rodent strains and opioids. The present study examined the influence of estrous cycle and gonadal hormone depletion (ovariectomy) on thermal nociception and opioid antinociception in female F344, Lewis, Long Evans, and Wistar rats. Estrous cycle-dependent differences in nociceptive sensitivity were not observed in any of the strains. Ovariectomy decreased nociceptive sensitivity relative to their intact female counterparts. In normal cycling females, morphine and buprenorphine were generally most potent in metestrus and proestrus and least potent in estrus. The magnitude of these differences was consistently larger with buprenorphine. Ovariectomy increased the antinociceptive potency of morphine and buprenorphine, with this effect also being larger with buprenorphine. These data suggest that in adult females of a number of rat strains, estrous cycle and gonadal hormone depletion modulate the antinociceptive potency of opioids, with the magnitude of this effect being dependent on the type of opioid. In contrast, depletion of gonadal hormones, but not estrous cycle, modulates thermal nociceptive sensitivity in adult female rats. PERSPECTIVE: Gonadal hormones influence opioid antinociception, and this effect is apparent across different genetic backgrounds. These results suggest that the phase of the menstrual cycle might alter the effectiveness of certain opioids administered to relieve pain in women.
Asunto(s)
Analgésicos Opioides/farmacología , Resistencia a Medicamentos/fisiología , Ciclo Estral/fisiología , Hormonas Esteroides Gonadales/metabolismo , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Animales , Buprenorfina/farmacología , Regulación hacia Abajo/fisiología , Femenino , Morfina/farmacología , Ovariectomía , Ovario/metabolismo , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Estimulación Física , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Ratas Long-Evans , Ratas Wistar , Caracteres Sexuales , Especificidad de la Especie , Sensación Térmica/fisiologíaRESUMEN
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 micro-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.
Asunto(s)
Analgésicos Opioides/farmacología , Analgésicos/farmacología , Dimensión del Dolor/efectos de los fármacos , Farmacogenética/métodos , Caracteres Sexuales , Animales , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Dimensión del Dolor/métodos , Ratas , Ratas Endogámicas BN , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Ratas Endogámicas WKY , Ratas Long-Evans , Ratas Sprague-Dawley , Ratas Wistar , Especificidad de la EspecieRESUMEN
RATIONALE: 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 micro opioids etorphine and morphine; the low-efficacy micro 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.
Asunto(s)
Analgésicos Opioides/farmacología , Analgésicos/farmacología , Orquiectomía , Ovariectomía , Caracteres Sexuales , Animales , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Dimensión del Dolor/métodos , Ratas , Ratas Endogámicas F344 , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Especificidad de la EspecieRESUMEN
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 kappa opioid-induced antinociception using a series of kappa opioids that vary in their relative effectiveness. METHODS: In a warm-water (50, 52 and 55C) tail-withdrawal procedure, the antinociceptive effects of kappa 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 kappa 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 kappa opioids were generally more potent and effective as antinociceptive agents in males than females. Similar to data obtained with micro opioids, the magnitude of these sex differences was generally larger with the less effective kappa opioids and determined, in part, by rat strain and nociceptive stimulus intensity.