RESUMO
Activation of the dopaminergic mesolimbic reward circuit that originates in the ventral tegmental area (VTA) is postulated to preferentially suppress emotional responses to noxious stimuli, and presumably contributes to the addictive liability of strong analgesics. VTA dopamine neurons are activated via cholinergic afferents and microinjection of carbachol (cholinergic agonist) into VTA is rewarding. Here, we evaluated regional differences within VTA in the capacity of carbachol to suppress rats' affective response to pain (vocalization afterdischarges, VADs) and to support conditioned place preference (CPP) learning. As carbachol is a non-specific agonist, muscarinic and nicotinic receptor involvement was assessed by administering atropine (muscarinic antagonist) and mecamylamine (nicotinic antagonist) into VTA prior to carbachol treatment. Unilateral injections of carbachol (4µg) into anterior VTA (aVTA) and posterior VTA (pVTA) suppressed VADs and supported CPP; whereas, injections into midVTA failed to effect either VADs or CPP. These findings corroborate the hypothesis that the neural substrates underlying affective analgesia and reward overlap. However, the extent of the overlap was only partial. Whereas both nicotinic and muscarinic receptors contributed to carbachol-induced affective analgesia in aVTA, only muscarinic receptors mediated the analgesic action of carbachol in pVTA. The rewarding effects of carbachol are mediated by the activation of both nicotinic and muscarinic receptors in both aVTA and pVTA. The results indicate that analgesia and reward are mediated by separate cholinergic mechanisms within pVTA. Nicotinic receptor antagonism within pVTA failed to attenuate carbachol-induced analgesia, but prevented carbachol-induced reward. As addictive liability of analgesics stem from their rewarding properties, the present findings suggest that these processes can be neuropharmacologically separated within pVTA.
Assuntos
Analgesia , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Recompensa , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Atropina/farmacologia , Masculino , Mecamilamina/farmacologia , Antagonistas Muscarínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Limiar da Dor/efeitos dos fármacos , Ratos , Ratos Long-Evans , Área Tegmentar Ventral/metabolismoRESUMO
The medial thalamic parafascicular nucleus (PF) and the rostral anterior cingulate cortex (rACC) are implicated in the processing and suppression of the affective dimension of pain. The present study evaluated the functional interaction between PF and rACC in mediating the suppression of pain affect in rats following administration of morphine or carbachol (acetylcholine agonist) into PF. Vocalizations that occur following a brief noxious tailshock (vocalization afterdischarges) are a validated rodent model of pain affect, and were preferentially suppressed by injection of morphine or carbachol into PF. Vocalizations that occur during tailshock were suppressed to a lesser degree, whereas, spinal motor reflexes (tail flick and hindlimb movements) were only slightly suppressed by injection of carbachol into PF and unaffected by injection of morphine into PF. Blocking glutamate receptors in rACC (NMDA and non-NMDA) by injecting D-2-amino-5-phosphonovalerate (AP-5) or 6-cyano-7-nitroquinoxaline-2,3-dione disodium (CNQX) produced dose-dependent antagonism of morphine-induced increases in vocalization thresholds. Carbachol-induced increases in vocalization thresholds were not affected by injection of either glutamate receptor antagonist into rACC. The results demonstrate that glutamate receptors in the rACC contribute to the suppression of pain affect produced by injection of morphine into PF, but not to the suppression of pain affect generated by intra-PF injection of carbachol.
Assuntos
Afeto/fisiologia , Giro do Cíngulo/fisiologia , Núcleos Intralaminares do Tálamo/fisiologia , Inibição Neural/fisiologia , Dor/fisiopatologia , Receptores de Glutamato/fisiologia , Afeto/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Animais , Modelos Animais de Doenças , Giro do Cíngulo/anatomia & histologia , Giro do Cíngulo/efeitos dos fármacos , Núcleos Intralaminares do Tálamo/anatomia & histologia , Núcleos Intralaminares do Tálamo/efeitos dos fármacos , Masculino , Morfina/farmacologia , Vias Neurais/anatomia & histologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Dor/tratamento farmacológico , Dor/psicologia , Ratos , Ratos Long-Evans , Receptores de Glutamato/efeitos dos fármacosRESUMO
The antinociceptive action of morphine microinjected into the nucleus parafascicularis thalami (nPf) on pain behaviors organized at different levels of the neuraxis was examined in the rat. Behaviors organized at spinal (spinal motor reflexes, SMRs), medullary (vocalizations during shock, VDSs), and forebrain (vocalization afterdischarges, VADs) levels were elicited by noxious tailshock. Morphine administered into nPf generated dose-dependent increases in thresholds of VDS and VAD, but failed to elevate SMR thresholds. Increases in vocalization thresholds were reversed in a dose-dependent manner by the microinjection of the mu-opiate receptor antagonist, methylnaloxonium, into nPf. Results are discussed in terms of the relative influence of nPf-administered morphine on nociceptive processing at spinal versus supraspinal levels of the neuraxis.
Assuntos
Analgésicos Opioides/farmacologia , Morfina/farmacologia , Naloxona/análogos & derivados , Nociceptores/efeitos dos fármacos , Núcleos Talâmicos/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Limiar Diferencial/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eletrochoque , Masculino , Bulbo/fisiologia , Microinjeções , Naloxona/farmacologia , Prosencéfalo/fisiologia , Compostos de Amônio Quaternário , Ratos , Ratos Long-Evans , Receptores Opioides mu/antagonistas & inibidores , Medula Espinal/fisiologia , Núcleos Talâmicos/efeitos dos fármacos , Vocalização Animal/efeitos dos fármacos , Vocalização Animal/fisiologiaRESUMO
The bilateral administration of the serotonin receptor antagonist methysergide (2.5 microg, 5 microg, and 10 microg) into either the central nucleus of the amygdala (ACe) or nucleus parafascicularis thalami (nPf) produced dose-dependent inhibition of the antinociceptive action of ventrolateral periaqueductal gray (vPAG)-administered morphine. Unilateral administration of these doses of methysergide into either the ACe or nPf had no effect on morphine-induced antinociception. However, the combined unilateral administration of these doses of methysergide into the ACe and nPf produced dose-dependent inhibition of morphine antinociception that was identical to that observed after its bilateral administration into either site. This latter finding is interpreted as evidence that a functional interaction between the ACe and nPf supports the antinociceptive action of morphine administered into the vPAG.
Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Morfina/farmacologia , Inibição Neural/efeitos dos fármacos , Nociceptores/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Núcleos Talâmicos/efeitos dos fármacos , Animais , Mapeamento Encefálico , Dominância Cerebral/efeitos dos fármacos , Relação Dose-Resposta a Droga , Injeções , Masculino , Metisergida/farmacologia , Ratos , Ratos Long-EvansRESUMO
The relative contribution of serotonin (5HT) neurotransmission within the medulla (rostral ventromedial medulla) and forebrain (amygdaloid central nucleus and nucleus parafascicularis thalami) to the antinociceptive action of morphine microinjected into the ventrolateral periaqueductal gray (vPAG) was evaluated. The 5HT receptor antagonist methysergide was microinjected into the medulla, forebrain, (or both) after injection of morphine into the vPAG. The contribution of 5HT to the antinociceptive action of morphine was observed to depend on (a) the dose of morphine administered into the vPAG, (b) the site(s) at which methysergide was administered, and (c) the level of the neuraxis at which the behavioral assay was organized. Results of the present study were combined with those of previous studies from this laboratory and presented as a model of the mechanisms by which morphine administered into the vPAG generates its antinociceptive action.
Assuntos
Tonsila do Cerebelo/metabolismo , Analgésicos Opioides/farmacologia , Bulbo/metabolismo , Morfina/farmacologia , Limiar da Dor/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Serotonina/metabolismo , Tálamo/metabolismo , Analgésicos Opioides/administração & dosagem , Animais , Masculino , Metisergida/farmacologia , Modelos Biológicos , Morfina/administração & dosagem , Ratos , Ratos Long-Evans , Antagonistas da Serotonina/farmacologiaRESUMO
The capacity of serotonin and norepinephrine to elevate the thresholds of spinal motor reflexes (SMRs), vocalizations during shock (VDSs), and vocalization afterdischarges (VADs) when administered into the spinal subarachnoid space was evaluated. Both monoamines generated dose-dependent increases in the thresholds of all 3 responses. The minimum effective doses of serotonin and norepinephrine that elevated all 3 response thresholds were 40 micrograms and 1 microgram respectively. Monoamine-induced increases in response thresholds were reversed by the intrathecal administration of their corresponding receptor antagonists (phentolamine or methysergide). Threshold increases generated by serotonin were also partially reduced by phentolamine. These results indicate that dorsal horn neurons that underlie flexion reflex generation (SMR) and the rostral transmission of pain information (VDS and VAD) have similar thresholds of inhibition to spinopetal monoaminergic projections.
Assuntos
Encéfalo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Norepinefrina/farmacologia , Limiar da Dor/efeitos dos fármacos , Reflexo/efeitos dos fármacos , Serotonina/farmacologia , Medula Espinal/efeitos dos fármacos , Vocalização Animal/efeitos dos fármacos , Vias Aferentes/efeitos dos fármacos , Animais , Mapeamento Encefálico , Relação Dose-Resposta a Droga , Gânglios Espinais/efeitos dos fármacos , Injeções Espinhais , Masculino , Inibição Neural/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , RatosRESUMO
The capacity of morphine microinjected into the ventrolateral periaqueductal gray (vPAG) to elevate the thresholds of spinal motor reflexes (SMRs), vocalizations during shock (VDSs) and vocalization afterdischarges (VADs) was challenged by the intrathecal administration of receptor antagonists to serotonin (methysergide), norepinephrine (phentolamine) and mu-opiates (naloxone). Methysergide and phentolamine were equipotent in reversing increases in SMR thresholds. The efficacy of these antagonists to reduce increases in VDS and VAD thresholds was dependent on the dose of morphine administered into the vPAG. These results indicate that the dose of morphine administered into the vPAG determines the contribution of spinopetal projections in inhibiting dorsal horn neurons involved in reflex generation versus the rostral transmission of pain information. A hypothesis is offered regarding the mechanisms by which vPAG administered morphine suppresses nociceptive transmission through different levels of the neuraxis.
Assuntos
Morfina/farmacologia , Neurônios Motores/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Reflexo/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Vocalização Animal/efeitos dos fármacos , Animais , Mapeamento Encefálico , Relação Dose-Resposta a Droga , Eletrochoque , Gânglios Espinais/efeitos dos fármacos , Masculino , Metisergida/farmacologia , Microinjeções , Naloxona/farmacologia , Vias Neurais/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Fentolamina/farmacologia , Ratos , Receptores Adrenérgicos/efeitos dos fármacos , Receptores Adrenérgicos/fisiologia , Receptores Opioides mu/efeitos dos fármacos , Receptores Opioides mu/fisiologia , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/fisiologiaRESUMO
Presentation of a 6-s light conditional stimulus (CS) that overlapped with a 1-s tailshock unconditional stimulus (US) generated audible conditional vocalization responses (VCRs) during the CS period. The rate of conditioning was observed to be directly related to the intensity of the tailshock US (0.15 mA-0.80 mA). The amplitude, duration, and number of VCRs was also directly related to US intensity, whereas the latency of VCRs from CS onset was inversely related to US intensity. VCRs were not observed in rats given explicitly unpaired presentations of CS and US (0.80 mA). The capacity of tailshock to support development of VCRs was found to depend on its capacity to elicit vocalization afterdischarges (VADs). Sonographic analysis of vocalizations revealed that VCRs and VADs share spectrographic characteristics. Results are discussed in terms of VCRs' providing a model system for analyzing the fear of pain and its suppression.
Assuntos
Condicionamento Clássico/fisiologia , Medo/fisiologia , Limiar da Dor/fisiologia , Vocalização Animal/fisiologia , Animais , Nível de Alerta/fisiologia , Aprendizagem por Associação/fisiologia , Diencéfalo/fisiologia , Sistema Límbico/fisiologia , Masculino , Motivação , Nociceptores/fisiologia , Ratos , Espectrografia do SomRESUMO
The relative influence of morphine microinjected into the periaqueductal gray, ventral medulla (nucleus raphé magnus or nucleus reticularis gigantocellularis), or spinal subarachnoid space on the thresholds of responses organized at spinal (spinal motor reflexes, SMRs), medullary (vocalizations elicited during shock, VDSs), and rhinencephalic-diencephalic (vocalization after discharges, VADs) levels of the neuraxis was assessed. Dose-dependent increases in response thresholds differed with the site of morphine injection. These results indicate that the mu-opiate-receptor-linked systems in the mesencephalon, medulla, and spinal cord exert differential antinociceptive effects on pain behaviors organized at different levels of the neuraxis. A hypothesis is offered regarding the mechanisms through which morphine inhibits nociceptive transmission through various levels of the CNS. VADs are promoted as a model system for analyzing the affective-motivational dimension of the pain experience.
Assuntos
Bulbo/efeitos dos fármacos , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Reflexo/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Vocalização Animal/efeitos dos fármacos , Afeto/efeitos dos fármacos , Animais , Mapeamento Encefálico , Relação Dose-Resposta a Droga , Eletrochoque , Injeções Intraventriculares , Injeções Espinhais , Masculino , Microinjeções , Motivação , Naloxona/farmacologia , Ratos , Tempo de Reação/efeitos dos fármacos , Limiar Sensorial/efeitos dos fármacos , Espaço Subaracnóideo/efeitos dos fármacosRESUMO
The relative influence of systemically administered morphine, fentanyl, and diazepam on the thresholds of spinal motor reflexes (SMRs), vocalizations elicited during stimulation (VDSs), and vocalization afterdischarges (VADs) was assessed. Responses were elicited by applying graded electric current to the tail. Performance (latency and amplitude) of all three responses was monitored to determine whether elevations in threshold were confounded by performance decrements. All three drugs were found to elevate VAD thresholds more readily than VDS and SMR thresholds. VADs were also most susceptible to the deleterious effects of these drugs on motor performance. Nevertheless, across the dose range of morphine and fentanyl that elevated thresholds of all three responses without disrupting the performance of any response, the order of susceptibility to threshold increases remained VAD, VDS, and SMR. Diazepam also elevated VAD thresholds more readily than VDS thresholds across a dose range that failed to disrupt performance of either response. SMR thresholds were only elevated by diazepam when administered in doses that significantly disrupted performance. Results are discussed in terms of supporting the validity of VADs as a model of the affective-motivational dimension of pain.
Assuntos
Diazepam/farmacologia , Fentanila/farmacologia , Morfina/farmacologia , Reflexo/efeitos dos fármacos , Vocalização Animal/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Eletrochoque , Feminino , Motivação , Neurônios Aferentes/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Cauda/fisiologiaRESUMO
Unconditional responses (URs) of the rat that predict 1-trial, step-through passive avoidance conditioning were identified. The URs examined were spinal motor reflexes (SMRs) and vocalization afterdischarges (VADs) generated by tailshock. In Experiment 1, SMR and VAD thresholds were determined following systemic administration of saline or morphine sulfate. Experiment 2 revealed that the capacity of these tailshocks to support conditioning covaried with the probability that VADs were elicited and were independent of the proportion of SMRs that were generated. This pattern of conditioning was not a consequence of either morphine-induced memory deficts or its induction of state-dependent learning (Experiment 3). The results are consistent with the 2-process theories of J. Konorski (1967) and A. R. Wagner & S. E. Brandon (1989) in which the unconditional stimulus is viewed as being composed of separable but interrelated epicritic-sensory and protopathic-emotive attributes.
Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Clássico/fisiologia , Atividade Motora/fisiologia , Limiar da Dor/fisiologia , Reflexo/fisiologia , Vocalização Animal/fisiologia , Animais , Eletrochoque , Feminino , Inibição Neural/fisiologia , Ratos , Tempo de Reação/fisiologia , Medula Espinal/fisiologiaRESUMO
The tail flick withdrawal reflex (TFR) was generated by applying graded electric current to the tail of intact and spinally transected rats. In Experiment 1, separate groups of rats were tested 1, 3, 7, 10, 14, or 21 days after spinal transection. The latency, amplitude, and magnitude of the TFR was highly related to current intensity in both intact and spinal animals. However, the TFR changed dramatically as a function of the number of days between spinalization and TFR measurement. Compared to intact controls, the current intensity at which TFR was initiated (threshold) in spinal rats was elevated 1 and 3 days after transection, did not differ at 7 and 10 days, and was reduced at 14 and 21 days. Latency of TFR in spinal rats did not differ from controls 1 day after transection, but decreased steadily thereafter. Amplitude and magnitude of TFR in spinal rats remained depressed, but did show recovery toward control levels as the interval between transection and testing increased. Changes in the TFR of spinal rats was correlated with recovery of tailpinch-elicited hindlimb withdrawal. Experiment 2 demonstrated that the dose-response curve relating systemic morphine treatment to increases in TFR thresholds was shifted to the right in chronic spinal rats. Threshold increases in both spinal and intact rats were not necessarily accompanied by changes in TFR performance. These experiments establish the segmental organization of tailshock-elicited TFR and supports its use as a measure of nociceptive transmission at spinal levels.
Assuntos
Nociceptores/fisiologia , Reflexo/fisiologia , Medula Espinal/fisiologia , Transmissão Sináptica/fisiologia , Vias Aferentes/efeitos dos fármacos , Vias Aferentes/fisiologia , Animais , Nível de Alerta/efeitos dos fármacos , Nível de Alerta/fisiologia , Relação Dose-Resposta a Droga , Eletrochoque , Feminino , Morfina/farmacologia , Nociceptores/efeitos dos fármacos , Ratos , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Reflexo/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Cauda/inervaçãoRESUMO
The present study describes a wheel turn/tail flick paradigm that was designed to simultaneously assess nociceptive thresholds of responses organized at spinal and supraspinal levels of the CNS in the rat. The paradigm involves training rats to perform an operant wheel turn response in order to escape current applied to the tail. Thresholds for the supraspinally organized escape response and the spinally organized tail flick reflex were determined via the psychophysical method of constant stimuli. Response latencies for wheel turn escape and tail flick were recorded to determine whether changes in nociceptive thresholds were confounded with changes in motor performance. The systemic administration of 3 mg/kg morphine sulfate elevated thresholds for both responses, but escape thresholds were elevated to a greater degree than tail flick thresholds. Because response latencies at threshold were not affected by morphine treatment, it appears that performance deficits did not contribute to the increase in thresholds. Advantage of these psychophysical procedures in assessing nociceptive responding in animals are discussed.
Assuntos
Reação de Fuga/efeitos dos fármacos , Morfina/farmacologia , Nociceptores/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Animais , Masculino , Psicofísica , Ratos , Ratos Endogâmicos , Limiar Sensorial/efeitos dos fármacosRESUMO
The relation between long-term decrements of the acoustic startle response in rats and the development of freezing behavior during habituation training was examined. Freezing behavior developed over the initial trials of habituation training, and the rate of long-term response decrements was found to be inversely related to the development of freezing. Manipulations (neurological or behavioral) that either reduced the level of freezing or retarded its development promoted startle response decrements. In Experiment 1, rats receiving electrolytic lesions of the ventrolateral periaqueductal gray demonstrated both accelerated long-term startle response decrements and retarded development of freezing behavior. In Experiment 2, preexposure to the startle apparatus (i.e., latent inhibition) accelerated long-term startle decrements and inhibited development of freezing. In Experiment 3, exposure to the startle apparatus following initial habituation training (i.e., extinction) reduced both freezing behavior and startle response amplitudes. The results are discussed in terms of the influence of Pavlovian fear conditioning on long-term habituation of the acoustic startle response.
Assuntos
Nível de Alerta/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Habituação Psicofisiológica/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Reflexo de Sobressalto/fisiologia , Animais , Mapeamento Encefálico , Dominância Cerebral/fisiologia , Masculino , Atividade Motora/fisiologia , Ratos , Ratos EndogâmicosRESUMO
Chronic decerebrate rats, maintained in good condition for 31-84 postoperative days, showed significant within-session habituation of the acoustic startle response. However, they showed no habituation over days under conditions that produced significant response deficits in controls. The decerebrates' stimulus-provoked response deficits may have endured for up to 40 min between sessions, and they were apparently more than normally susceptible to stimulus-provoked sensitization. The data are consistent with intrinsic models which assume that the mechanisms for short-term habituation are intrinsic to the stimulus-response (S-R) pathway in the lower brain stem. On the other hand, relatively permanent long-term habituation of the acoustic startle response must be mediated by extrinsic mechanisms rostral to the S-R pathway which superimpose an inhibitory influence on that pathway.