RESUMEN
Clinical studies have shown that agonist-antagonist opioid analgesics that produce their analgesic effect via action on the kappa-opioid receptor, produce a delayed-onset anti-analgesia in men but not women, an effect blocked by co-administration of a low dose of naloxone. We now report the same time-dependent anti-analgesia and its underlying mechanism in an animal model. Using the Randall-Selitto paw-withdrawal assay in male rats, we found that nalbuphine, pentazocine, and butorphanol each produced analgesia during the first hour followed by anti-analgesia starting at â¼90min after administration in males but not females, closely mimicking its clinical effects. As observed in humans, co-administration of nalbuphine with naloxone in a dose ratio of 12.5:1 blocked anti-analgesia but not analgesia. Administration of the highly selective kappa-opioid receptor agonist U69593 produced analgesia without subsequent anti-analgesia, and confirmed by the failure of the selective kappa antagonist nor-binaltorphimine to block nalbuphine-induced anti-analgesia, indicating that anti-analgesia is not mediated by kappa-opioid receptors. We therefore tested the role of other receptors in nalbuphine anti-analgesia. Nociceptin/orphanin FQ (NOP) and sigma-1 and sigma-2 receptors were chosen on the basis of their known anti-analgesic effects and receptor binding studies. The selective NOP receptor antagonists, JTC801, and J-113397, but not the sigma receptor antagonist, BD 1047, antagonized nalbuphine anti-analgesia. Furthermore, the NOP receptor agonist NNC 63-0532 produced anti-analgesia with the same delay in onset observed with the three agonist-antagonists, but without producing preceding analgesia and this anti-analgesia was also blocked by naloxone. These results strongly support the suggestion that clinically used agonist-antagonists act at the NOP receptor to produce anti-analgesia.
Asunto(s)
Analgésicos/farmacología , Antagonistas de Narcóticos/farmacología , Péptidos Opioides/metabolismo , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Análisis de Varianza , Animales , Bencenoacetamidas , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Masculino , Nalbufina/farmacología , Naloxona/farmacología , Unión Proteica/efectos de los fármacos , Pirrolidinas , Ratas , Ratas Sprague-Dawley , Diferenciación Sexual , NociceptinaRESUMEN
In heterozygous mice, attenuation of G-protein-coupled receptor kinase 2 (GRK2) level in nociceptors is associated with enhanced and prolonged inflammatory hyperalgesia. To further elucidate the role of GRK2 in nociceptor function we reversibly decreased GRK2 expression using intrathecal antisense oligodeoxynucleotide (AS-ODN). GRK2 AS-ODN administration led to an enhanced and prolonged hyperalgesia induced by prostaglandin E(2), epinephrine and carrageenan. Moreover, this effect persisted unattenuated 2weeks after the last dose of antisense, well after GRK2 protein recovered, suggesting that transient attenuation of GRK2 produced neuroplastic changes in nociceptor function. Unlike hyperalgesic priming induced by transient activation of protein kinase C epsilon (PKCε), (Aley et al., 2000; Parada et al., 2003b), the enhanced and prolonged hyperalgesia following attenuation of GRK2 is PKCε- and cytoplasmic polyadenylation element binding protein (CPEB)-independent and is protein kinase A (PKA)- and Src tyrosine kinase (Src)-dependent. Finally, rats treated with GRK2 AS-ODN exhibited enhanced and prolonged hyperalgesia induced by direct activation of second messengers, adenyl cyclase, Epac or PKA, suggesting changes downstream of G-protein-coupled receptors. Because inflammation can produce a decrease in GRK2, such a mechanism could help explain a predilection to develop chronic pain, after resolution of acute inflammation.
Asunto(s)
Quinasa 2 del Receptor Acoplado a Proteína-G/genética , Inflamación/genética , Nociceptores/metabolismo , Dolor/genética , Animales , Western Blotting , Quinasa 2 del Receptor Acoplado a Proteína-G/biosíntesis , Gliceraldehído-3-Fosfato Deshidrogenasas/metabolismo , Hiperalgesia/genética , Hiperalgesia/psicología , Inflamación/complicaciones , Masculino , Oligodesoxirribonucleótidos Antisentido/farmacología , Dolor/etiología , Umbral del Dolor , Fosfolipasa C beta/biosíntesis , Fosfolipasa C beta/genética , Proteína Quinasa C-epsilon/fisiología , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Ratas , Ratas Sprague-Dawley , Sistemas de Mensajero Secundario/fisiologíaRESUMEN
When comparing a cumulative dose-response curve for endothelin-1 (ET-1)-induced mechanical hyperalgesia to the effect of individual doses (1 ng, 10 ng, 100 ng, and 1 µg) administered in separate groups of rats, a marked difference was observed in the peak magnitude of hyperalgesia. Hyperalgesia was measured as decrease in the threshold for mechanically-induced withdrawal of the hind paw. The cumulative dosing protocol produced markedly greater maximum hyperalgesia. To determine whether this was due to the cumulative dosing protocol or to the repeated exposure to the mechanical test stimulus, we evaluated the impact of repeated testing on ET-1-induced mechanical hyperalgesia. While ET-1-induced mechanical hyperalgesia was dose- and time-dependent, repeated testing of nociceptive threshold, at 5 min intervals, following a single dose of ET-1, produced further decrease in nociceptive threshold. This mechanical stimulation-induced enhancement of ET-1 hyperalgesia lasted only 3-4 h, while the hyperalgesia lasted in excess of 5 days. The stimulation-enhanced hyperalgesia also occurred after a second injection of ET-1, administered 24 h after the initial dose. That this phenomenon is unique to ET-1 is suggested by the observation that while five additional, direct-acting hyperalgesic agents-prostaglandin E2 (PGE2), nerve growth factor (NGF), glia-derived neurotrophic factor (GDNF), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα)-induced robust mechanical hyperalgesia, none produced mechanical stimulation-enhanced hyperalgesia.
Asunto(s)
Endotelina-1/farmacología , Hiperalgesia/inducido químicamente , Estimulación Física/métodos , Animales , Dinoprostona/farmacología , Relación Dosis-Respuesta a Droga , Endotelina-1/administración & dosificación , Interleucina-6/farmacología , Masculino , Factores de Crecimiento Nervioso/farmacología , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Taquifilaxis , Factores de Tiempo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
In studies of the role of primary afferent nociceptor plasticity in the transition from acute to chronic pain we recently reported that exposure to unpredictable sound stress or a prior inflammatory response induces long-term changes in the second messenger signaling pathway, in nociceptors, mediating inflammatory hyperalgesia; this change involves a switch from a G(s)-cAMP-PKA to a G(i)-PKCepsilon signaling pathway. To more directly study the role of G(i) in mechanical hyperalgesia we evaluated the nociceptive effect of the G(i) activator, mastoparan. Intradermal injection of mastoparan in the rat hind paw induces dose-dependent (0.1 ng-1 microg) mechanical hyperalgesia. The highly selective inhibitors of G(i), pertussis toxin, and of protein kinase C epsilon (PKCepsilon), PKCepsilonV(1-2), both markedly attenuate mastoparan-induced hyperalgesia in stressed rats but had no effect on mastoparan-induced hyperalgesia in unstressed rats. Similar effects were observed, at the site of nociceptive testing, after recovery from carrageenan-induced inflammation. These studies provide further confirmation for a switch to a G(i)-activated and PKCepsilon-dependent signaling pathway in primary mechanical hyperalgesia, induced by stress or inflammation.
Asunto(s)
Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo , Hiperalgesia/metabolismo , Nociceptores/metabolismo , Proteína Quinasa C-epsilon/metabolismo , Transducción de Señal/fisiología , Animales , Relación Dosis-Respuesta a Droga , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/complicaciones , Inflamación/complicaciones , Péptidos y Proteínas de Señalización Intercelular , Irritantes , Masculino , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Péptidos , Ratas , Ratas Sprague-Dawley , Sistemas de Mensajero Secundario , Transducción de Señal/efectos de los fármacos , Estrés Psicológico/complicaciones , Venenos de AvispasRESUMEN
The type 1 chemokine monocyte chemoattractant protein (MCP-1) has been implicated in the generation of inflammatory and neuropathic pain, but the underlying mechanism remains poorly understood. Here we show that mechanical hyperalgesia induced by intradermal injection of MCP-1 in the rat is blocked by the intrathecal administration of isolectin B4 (IB4)-saporin, a selective neurotoxin for IB4(+)/Ret(+)-nociceptors. MCP-1-induced hyperalgesia is also attenuated by intrathecal antisense oligodeoxynucleotides targeting mRNA for versican, a molecule that binds MCP-1 and that also renders the Ret-expressing nociceptors IB4-positive (+). Finally, peripheral administration of ADAMTS-4 or chondroitinase ABC, two enzymes that disrupt versican integrity by the degradation of the versican core-protein or its chondroitin sulfate glycosaminoglycan side chains, respectively, also attenuated MCP-1 hyperalgesia at the site of nociceptive testing. We suggest that versican's glycosaminoglycan side chains present MCP-1 to a CCR2 expressing cell type in the skin that, in turn, selectively activates IB4(+)/Ret(+) nociceptors, thereby contributing to enhanced mechanical sensitivity under inflammatory conditions.
Asunto(s)
Quimiocina CCL2 , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Versicanos/metabolismo , Proteínas ADAM/farmacología , Proteína ADAMTS4 , Análisis de Varianza , Animales , Condroitina ABC Liasa/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Hiperalgesia/tratamiento farmacológico , Lectinas/uso terapéutico , Masculino , Neurotoxinas/uso terapéutico , Oligorribonucleótidos Antisentido/uso terapéutico , Dimensión del Dolor/métodos , Umbral del Dolor/efectos de los fármacos , Procolágeno N-Endopeptidasa/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas Inactivadoras de Ribosomas Tipo 1/uso terapéutico , Saporinas , Factores de Tiempo , Versicanos/genéticaRESUMEN
Small-fiber painful peripheral neuropathy, a complication of chronic ethanol ingestion, is more severe in women. In the present study, we have replicated this clinical finding in the rat and evaluated for a role of estrogen and second messenger signaling pathways. The alcohol diet (6.5% ethanol volume:volume in Lieber-DeCarli formula) induced hyperalgesia with more rapid onset and severity in females. Following ovariectomy, alcohol failed to induce hyperalgesia in female rats, well past its time to onset in gonad intact males and females. Estrogen replacement reinstated alcohol neuropathy in the female rat. The protein kinase A (PKA) inhibitor (Walsh inhibitor peptide, WIPTIDE) only attenuated alcohol-induced hyperalgesia in female rats. Inhibitors of protein kinase Cepsilon (PKCepsilon-I) and extracellular-signal related kinase (ERK) 1/2 (2'-amino-3'-methoxyflavone (PD98059) and 1,4-diamino-2, 3-dicyano-1, 4-bis (2-aminophenylthio) butadiene (U0126)) attenuated hyperalgesia in males and females, however the degree of attenuation produced by PKCepsilon-I was much greater in females. In conclusion, estrogen plays an important role in the expression of pain associated with alcohol neuropathy in the female rat. In contrast to inflammatory hyperalgesia, in which only the contribution of PKCepsilon signaling is sexually dimorphic, in alcohol neuropathy PKA as well as PKCepsilon signaling is highly sexually dimorphic.
Asunto(s)
Alcoholes , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Estrógenos/fisiología , Neuralgia/inducido químicamente , Proteína Quinasa C-epsilon/fisiología , Caracteres Sexuales , Análisis de Varianza , Animales , Interacciones Farmacológicas , Inhibidores Enzimáticos/administración & dosificación , Femenino , Hiperalgesia/inducido químicamente , Hiperalgesia/enzimología , Hiperalgesia/fisiopatología , Masculino , Neuralgia/enzimología , Neuralgia/fisiopatología , Ovariectomía/métodos , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Noxious (i.e. painful) stimulation in the rat induces profound heterosegmental antinociception as demonstrated by the ability of either thermal stimulation (50 degrees C water) or subdermal capsaicin injection in the hindpaw to attenuate the nociceptive trigeminal jaw-opening reflex. Importantly, noxious stimulus-induced antinociception (NSIA) is mediated by endogenous opioids (as well as other neurotransmitters) in nucleus accumbens, as indicated by the ability of intra-accumbens administration of mu- or delta-opioid receptor antagonists to block NSIA. Although noxious peripheral stimulation is known to release excitatory neurotransmitters such as glutamate at the level of the spinal cord, the present study was designed to test the hypothesis that NSIA depends on further activation of spinal inhibitory receptors. This hypothesis was based on findings that inhibition of spinal processing (e.g. intrathecal local anaesthetic administration) also produces heterosegmental antinociception mediated by endogenous opioids in nucleus accumbens. Thus, to reconcile the paradoxical findings that both spinal excitation and inhibition appear to activate the same nucleus accumbens opioid-mediated antinociceptive mechanism, we investigated whether spinal administration of antagonists for inhibitory receptors would block the antinociceptive effect of subdermal capsaicin. We report that spinal administration of selective antagonists for mu-opioid (Cys2, Tyr3, Orn5, Pen7amide), kappa-opioid (nor-binaltorphimine), GABA-A (bicuculline), GABA-B (CGP 35348) and glycine (strychnine) receptors significantly reduced NSIA. The selective delta-opioid receptor antagonist naltrindole had no significant effect. These results, together with our previous findings, suggest that peripheral noxious stimuli release endogenous opioids, GABA and glycine in the spinal cord which, in turn, inhibit tonic pronociceptive spinal activity to produce heterosegmental antinociception mediated in nucleus accumbens.
Asunto(s)
Inhibición Neural/fisiología , Dolor/fisiopatología , Médula Espinal/fisiopatología , Animales , Bicuculina/farmacología , Capsaicina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Electrodos Implantados , Electromiografía , Antagonistas del GABA , Glicinérgicos/farmacología , Masculino , Modelos Neurológicos , Antagonistas de Narcóticos/farmacología , Núcleo Accumbens/fisiopatología , Compuestos Organofosforados/farmacocinética , Dolor/inducido químicamente , Dimensión del Dolor/métodos , Estimulación Física , Ratas , Ratas Sprague-Dawley , Receptores Opioides kappa/antagonistas & inhibidores , Receptores Opioides kappa/efectos de los fármacos , Receptores Opioides mu/antagonistas & inhibidores , Receptores Opioides mu/efectos de los fármacos , Médula Espinal/efectos de los fármacos , Estricnina/farmacologíaRESUMEN
It is known that the level of activity in nociceptive primary afferent nerve fibers increases in neuropathic conditions that produce pain, but changes in the temporal patterning of action potentials have not been analyzed in any detail. Because the patterning of action potentials in sensory nerve fibers might play a role in the development of pathological pain states, we studied patterning of mechanical stimulus-evoked action potential trains in nociceptive primary afferents in a rat model of vincristine-induced painful peripheral neuropathy. Systemic administration of vincristine (100 microg/kg) caused approximately half the C-fiber nociceptors to become markedly hyperresponsive to mechanical stimulation. Instantaneous frequency plots showed that vincristine induced an irregular pattern of action-potential firing in hyperresponsive C-fibers, characterized by interspersed occurrences of high- and low-frequency firing. This pattern was associated with an increase in the percentage of interspike intervals 100-199 ms in duration compared with that in C-fibers from control rats and vincristine-treated C-fibers that did not become hyperresponsive. Variability in the temporal pattern of action potential firing was quantified by determining the coefficient of variability (CV2) for adjacent interspike intervals. This analysis revealed that vincristine altered the pattern of action-potential timing, so that combinations of higher firing frequency and higher variability occurred that were not observed in control fibers. The abnormal temporal structure of nociceptor responses induced by vincristine in some C-fiber nociceptors could contribute to the pathogenesis of chemotherapy-induced neuropathic pain, perhaps by inducing activity-dependent post-synaptic effects in sensory pathways.
Asunto(s)
Vías Aferentes/efectos de los fármacos , Fibras Nerviosas Amielínicas/efectos de los fármacos , Neuralgia/inducido químicamente , Neuralgia/fisiopatología , Nociceptores/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Vincristina/efectos adversos , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/fisiología , Vías Aferentes/fisiología , Animales , Modelos Animales de Enfermedad , Masculino , Fibras Nerviosas Amielínicas/fisiología , Neuralgia/patología , Nociceptores/fisiología , Enfermedades del Sistema Nervioso Periférico/patología , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
Neither the etiology of muscle-related temporomandibular disorders (TMD) nor the reason for the disproportionate number of women suffering from these disorders is well-established. We tested the hypothesis that physiologically relevant exercise (i.e., chewing bubble gum for 6 min) increases masticatory muscle pain in patients, but not in asymptomatic control subjects, and that female patients experience a significantly greater increase than males. Chewing increased pain in both female and male patients and, unexpectedly, also in female control subjects. One hour after chewing, the pain remained above pre-test levels for female patients but not for the other groups. Thus, sex differences in chewing-induced pain were found in control subjects but not as hypothesized in patients. Because chewing-induced masticatory muscle pain was significantly greater in female control subjects than in males, and persisted longer in female patients than in males, these results suggest greater susceptibility in women.
Asunto(s)
Dolor Facial/fisiopatología , Músculo Masetero/fisiopatología , Caracteres Sexuales , Síndrome de la Disfunción de Articulación Temporomandibular/fisiopatología , Adulto , Análisis de Varianza , Estudios de Casos y Controles , Susceptibilidad a Enfermedades , Femenino , Humanos , Masculino , Masticación , Dimensión del Dolor , Rango del Movimiento ArticularRESUMEN
The nucleus accumbens, as part of the mesolimbic dopaminergic reward pathway, mediates both addiction to and withdrawal from substances of abuse. In addition, activity of substances of abuse such as opioids in the nucleus accumbens has been implicated in pain modulation. Because nucleus accumbens nicotinic receptors are important in nicotine addiction and because nicotinic activity can interact with opioid action, we investigated the contribution of nucleus accumbens nicotinic receptors to opioid-mediated analgesia/antinociception. The response of the nociceptive jaw-opening reflex to opioids was studied in the rat, both before and during chronic nicotine exposure. In nicotine-naive rats, intra-accumbens injection of the nicotinic receptor antagonist mecamylamine blocked antinociception produced by either systemic morphine, intra-accumbens co-administration of a mu- and a delta-opioid receptor agonist, or noxious stimulation (i.e., subdermal capsaicin in the hindpaw); intra-accumbens mecamylamine alone had no effect. The antinociceptive effect of either morphine or noxious stimulation was unchanged during nicotine tolerance; however, intra-accumbens mecamylamine lost its ability to block antinociception produced by either treatment. Intra-accumbens mecamylamine by itself precipitated significant hyperalgesia in nicotine-tolerant rats which could be suppressed by noxious stimulation as well as by morphine. These results indicate that nucleus accumbens nicotinic receptors play an important role in both opioid- and noxious stimulus-induced antinociception in nicotine-naive rats. This role was attenuated in the nicotine-dependent state. The suppression of withdrawal hyperalgesia by noxious stimulation suggests that pain can ameliorate the symptoms of withdrawal, thus suggesting a possible mechanism for pain-seeking behavior.
Asunto(s)
Hiperalgesia/metabolismo , Narcóticos/farmacología , Nicotina/farmacología , Núcleo Accumbens/efectos de los fármacos , Receptores Nicotínicos/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/metabolismo , Tabaquismo/metabolismo , Analgesia , Animales , Capsaicina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Tolerancia a Medicamentos/fisiología , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Masculino , Mecamilamina/farmacología , Morfina/farmacología , Antagonistas Nicotínicos/farmacología , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/metabolismo , Síndrome de Abstinencia a Sustancias/fisiopatología , Tabaquismo/fisiopatologíaRESUMEN
We studied the influence of gender and gonadal hormones on modulation of tonic nociception exerted by vagal activity. In male rats, subdiaphragmatic vagotomy resulted in significantly reduced nociceptive behavior during phase 2 of the formalin test. Whereas gonadectomy alone had no effect, it completely eliminated the suppressive effect of subdiaphragmatic vagotomy; however, sex hormone replacement with either testosterone or dihydrotestosterone did not restore the ability of subdiaphragmatic vagotomy to suppress nociceptive behavior. These results suggest that, in males, a gonad-dependent but androgenic gonadal hormone-independent mechanism contributes to pronociceptive effects of vagal afferent activity. Although neither gonadectomy nor subdiaphragmatic vagotomy alone affected the response to formalin in females, gonadectomy plus vagotomy resulted in significantly reduced nociceptive behavior during phase 2. Reconstitution with 17 beta-estradiol implants in gonadectomized females not only prevented suppression of nociceptive behavior seen with gonadectomy plus vagotomy, but also led to increased nociceptive behavior in the interphase between phases 1 and 2. However, placement of 17 beta-estradiol implants in gonad-intact females had no effect on formalin-induced nociceptive behavior. The finding that estrogen produced an increase in nociceptive behavior in gonadectomized female rats after vagotomy but not in normal female rats (with intact gonads and subdiaphragmatic vagus) suggests that the interaction between estrogen and nociceptive afferent activity is suppressed by vagal function. In conclusion, a nonandrogenic action of testicular function in male rats and estrogen in females seems to influence the effect of vagal activity on formalin-induced nociceptive behavior.
RESUMEN
Nalbuphine, pentazocine, and butorphanol, mixed agonist/antagonist opioids that induce analgesia by acting predominantly at kappa opioid receptors, have recently been shown in single-dose studies to have greater analgesic efficacy in women than in men. In the current experiments, the first placebo controlled dose response study of opioid analgesic efficacy that examines for gender differences, nalbuphine (5, 10, or 20 mg) and placebo were evaluated in 62 men and 69 women for the treatment of moderate to severe postoperative pain following extraction of impacted wisdom teeth. In a randomized, open injection, double blind experimental design, pain intensity was recorded on a 10 cm visual analog scale (VAS) immediately prior to drug administration (baseline) and at 20 min intervals thereafter. Although responses to placebo were similar in men and women, for all doses of nalbuphine women exhibited significantly greater analgesic response than men, compatible with our previous results. Unexpectedly, men receiving the 5 mg dose of nalbuphine experienced significantly greater pain than those receiving placebo; only the 20 mg dose of nalbuphine in men produced significant analgesia compared to placebo. While a similar antianalgesic effect was not observed in women, only the 10 mg dose of nalbuphine produced significant analgesia compared to placebo. These results suggest that the optimal analgesic dose of nalbuphine for women is lower than the highest dose that can be safely administered. In contrast, the antianalgesic effect of nalbuphine suggests avoidance of its routine use for postoperative analgesia in men until further studies clarify this issue. Because gender differences in other mixed kappa agonists/antagonists (i.e. pentazocine and butorphanol) have previously been shown, these results may generally apply to this class of opioid analgesics.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Nalbufina/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Adulto , Análisis de Varianza , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Procedimientos Quirúrgicos Orales , Dimensión del Dolor , Dolor Postoperatorio/fisiopatología , Placebos , Receptores Opioides kappa , Caracteres Sexuales , Factores de TiempoRESUMEN
We tested the hypothesis that noxious stimuli induce pain modulation by activation of supraspinal structures. We found that intense noxious stimuli (i.e., subdermal injection of capsaicin or paw immersion in hot water) induced profound attenuation of the jaw-opening reflex in the anesthetized rat; forepaw subdermal capsaicin also elevated the mechanical hindpaw-withdrawal threshold in the awake rat. These antinociceptive effects were blocked by previous injection of either a dopamine antagonist (flupentixol) or an opioid antagonist (naloxone) into the nucleus accumbens. Additional experiments in anesthetized animals showed that the antinociceptive effect of noxious stimulation by either capsaicin (>/=100 micrograms) or hindpaw immersion in hot water (>/=45 degrees C for 4 min) correlated with the intensity of the stimulus. The maximal antinociceptive effect of capsaicin was similar in magnitude to that of a high dose of morphine (10 mg/kg) injected subcutaneously. Injection of the GABA(A)-receptor agonist muscimol, but not naloxone, into the rostroventral medulla, a major component of descending pain modulation systems, blocked capsaicin-induced antinociception. Although it is widely thought that painful stimuli may induce analgesia by activating forebrain structures, this is the first demonstration that such a mechanism exists. Furthermore, this mechanism can be engaged by naturalistic stimuli in awake animals. These observations imply that painful stimuli might under certain conditions be rewarding.
Asunto(s)
Analgesia/métodos , Sistema Límbico/fisiología , Bulbo Raquídeo/fisiología , Dolor/fisiopatología , Recompensa , Animales , Estimulación Eléctrica , Masculino , Vías Nerviosas/fisiología , Ratas , Ratas Sprague-DawleyRESUMEN
Activation of supraspinal gamma-aminobutyric acid-A (GABAA) receptors is known to result in antagonism of opioid analgesia. Since benzodiazepines enhance the action of GABA at GABAA receptors, we hypothesized that administration of these agents for preoperative sedation might antagonize the analgesic effects of opioids administered postoperatively. If so, then administration of the benzodiazepine antagonist flumazenil should enhance postoperative morphine analgesia. In a double-blind, placebo-controlled study of patients who received a preoperatively administered benzodiazepine (diazepam) for sedation and a postoperatively administered opioid (morphine) for analgesia, we investigated opioid-benzodiazepine interactions affecting postoperative dental pain. We found that flumazenil significantly enhanced morphine analgesia consistent with the hypothesis that the preoperatively administered benzodiazepine exerts an ongoing antianalgesic effect. In addition, we followed these patients over the first and second postoperative days to determine if there were differences between the drug groups in post-discharge pain, analgesic consumption, or side-effects. Participants receiving flumazenil reported significantly less post-discharge nausea and used significantly less ibuprofen. Since post-discharge pain levels were not significantly different, these results suggest that the patients receiving flumazenil required less analgesic medication to achieve a comparable level of pain control. In summary, our results indicate that the benzodiazepine antagonist flumazenil enhances morphine analgesia and decreases post-discharge side-effects as well as post-discharge need for analgesic medication.
Asunto(s)
Analgésicos Opioides/uso terapéutico , Flumazenil/uso terapéutico , Moduladores del GABA/uso terapéutico , Morfina/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Receptores de GABA-A/fisiología , Adulto , Analgésicos no Narcóticos/uso terapéutico , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Ansiolíticos , Diazepam , Método Doble Ciego , Sinergismo Farmacológico , Femenino , Flumazenil/administración & dosificación , Moduladores del GABA/administración & dosificación , Humanos , Ibuprofeno/uso terapéutico , Inyecciones Intravenosas , Masculino , Tercer Molar , Morfina/administración & dosificación , Morfina/efectos adversos , Dimensión del Dolor , Premedicación , Receptores de GABA-A/efectos de los fármacos , Extracción DentalRESUMEN
Sex differences in human responses to nociceptive stimuli and painful pathological conditions have generally indicated that women report higher pain levels or exhibit less tolerance than men for given stimulus intensities (reviewed in ref. 1 and 2). However, studies have not evaluated sex differences in analgesic responses. We recently reported that the opioid agonist-antagonist pentazocine, which acts predominantly at kappa-receptors, produced significantly better postoperative analgesia in females than in males in patients who underwent surgery for the removal of their third molars (wisdom teeth). In the current study, we evaluated the hypothesis that this sex difference is a characteristic of kappa-opioid agonism. In order to determine whether there are sex differences associated with kappa-opioid agonism, the analgesic efficacy of two other predominantly kappa-opioid analgesics, nalbuphine and butorphanol; was compared in males and females who underwent surgery for the removal of third molar teeth. We found that both nalbuphine and butorphanol produced significantly greater analgesia in females as compared with males. Considering our earlier findings, we conclude that kappa-opioid analgesia is greater in females than in males, probably reflecting a difference in kappa-opioid-activated endogenous pain modulating circuits.
Asunto(s)
Analgesia , Analgésicos Opioides/farmacología , Butorfanol/farmacología , Tercer Molar/cirugía , Nalbufina/farmacología , Caracteres Sexuales , Butorfanol/efectos adversos , Femenino , Humanos , Masculino , Nalbufina/efectos adversos , Narcóticos/metabolismo , Receptores Opioides kappa/metabolismo , Factores de TiempoRESUMEN
Gender difference in analgesia produced by the kappa-opiate pentazocine was investigated in a model of post-operative dental pain. In a recent study [Gordon et al., Neuroscience, 69 (1995) 345-349.] evaluating interaction between the GABAB agonist baclofen and opiates with respect to postoperative analgesia we found that females receiving pentazocine for the treatment of postoperative pain showed better analgesia than did males receiving similar treatment. To follow-up this result, we evaluated for the effect of gender on analgesia produced by pentazocine administered to participants not receiving another experimental medication. The analgesic response to pentazocine in ten females was compared to that in eight males. All participants were administered pentazocine after undergoing surgery for the removal of impacted third molars. We confirm our previous finding that pentazocine produces significantly greater analgesia in females than in males; no significant difference was observed in analgesia among females in different phases of the menstrual cycle.
Asunto(s)
Analgésicos Opioides/farmacología , Dolor Postoperatorio/tratamiento farmacológico , Pentazocina/farmacología , Receptores Opioides kappa/agonistas , Caracteres Sexuales , Adulto , Análisis de Varianza , Femenino , Humanos , Masculino , Ciclo Menstrual/efectos de los fármacos , Estudios Prospectivos , Diente/cirugíaRESUMEN
Opioid-GABAergic interactions for the treatment of post-operative pain were investigated in two double-blind, placebo-controlled experiments. We first studied the effect of pre-operatively administered baclofen, a GABAB receptor agonist, on the analgesia produced by intravenously administered morphine, a predominantly mu-opioid analgesic. In a separate trial, we studied the effect of baclofen on the analgesia produced by pentazocine, a predominantly kappa-opioid analgesic. While baclofen alone did not affect the level of post-operative pain, morphine analgesia was significantly enhanced by baclofen compared to placebo. In contrast, baclofen did not affect the level of pentazocine analgesia: however, females receiving pentazocine showed significantly greater analgesia than males.
Asunto(s)
Baclofeno/uso terapéutico , Morfina/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Adulto , Análisis de Varianza , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Masculino , Pentazocina/uso terapéutico , Factores de TiempoRESUMEN
Although interactions between opioids and adrenergic agonists in the treatment of pain have been demonstrated in humans, the contribution of specific adrenergic receptors in this interaction remains to be clarified. In a double-blind, placebo-controlled study in male patients with postoperative dental pain, we investigated the effect of preoperative administration of the alpha 2-adrenergic antagonist, yohimbine, on analgesia produced by postoperative intravenous morphine. Although yohimbine by itself did not affect the pain, the overall analgesic effect of morphine was significantly enhanced in the presence of yohimbine. This report is the first to demonstrate that an alpha 2-adrenergic antagonist enhances opiate analgesia in humans.
Asunto(s)
Antagonistas de Receptores Adrenérgicos alfa 2 , Analgésicos/uso terapéutico , Morfina/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Yohimbina/uso terapéutico , Adulto , Método Doble Ciego , Sinergismo Farmacológico , Humanos , Masculino , Dimensión del Dolor/efectos de los fármacos , Extracción DentalRESUMEN
Studies in mice and rats have shown that antinociception produced by intrathecal (i.t.) administration of opioids can be partially inhibited by intracerebroventricular (i.c.v.) administration of naloxone. In this study we tested the hypothesis that this inhibition by i.c.v. naloxone results from antagonism of supraspinal endogenous opioid-mediated antinociception produced by the action of i.t. opioids on an ascending antinociceptive pathway. In rats lightly anesthetized with urethane/alpha-chloralose, i.t. DAMGO, i.t. lidocaine, or spinal transection at T5-T6 all attenuated the trigeminal jaw opening reflex (JOR) (i.e., were antinociceptive), an effect that was antagonized in each case by i.c.v. naloxone. These findings support the suggestion that there exists a pathway that ascends from the spinal cord to a supraspinal site that tonically inhibits antinociception mediated by supraspinal opioids. When activity in this ascending pathway is suppressed (e.g., by i.t. opioids or local anesthetics or by spinal cord transection), antinociception mediated by supraspinal opioids is disinhibited. To determine the supraspinal site(s) at which endogenous opioid-dependent antinociception is evoked by i.t. opioids, we microinjected naloxone methiodide into several supraspinal sites. Microinjection of naloxone methiodide into nucleus accumbens but not into the rostral ventral medulla (RVM) or the periaqueductal gray matter (PAG) antagonized the suppression of the JOR produced by i.t. DAMGO or lidocaine. The possibility that this ascending pathway may represent a source of spinal input to mesolimbic circuitry involved in setting the state of sensorimotor reactivity to noxious stimuli is discussed.