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The extra-hypothalamic actions of corticotropin-releasing hormone (CRH) have been accorded an important role in coordinating responses to stressors and contributing to the consequences of drug abuse. Recent proposals suggest that CRH actions in the bed nucleus of the stria terminalis coordinate responses to tonic/unpredictable stressors whereas these actions in the central nucleus of the amygdala coordinate responses to phasic/predictable stressors. We used in situ hybridization histochemistry and site-specific microinjections of a CRH receptor antagonist to study the role of CRH in opiate withdrawal. Rats undergoing opiate withdrawal displayed clear behavioral and autonomic changes accompanied by hyperalgesia and increased plasma corticosterone. In situ hybridization of CRH mRNA revealed significant increases in the central nucleus of the amygdala but not in the bed nucleus of the stria terminalis among rats either chronically pre-treated with morphine, given an injection of naloxone, or both (precipitated withdrawal). An increase of CRH mRNA in the paraventricular nucleus of the hypothalamus was specific to rats undergoing withdrawal. Intracerebroventricular microinjection of the CRH receptor antagonist, alpha(h)CRH(9-41), reduced the severity of opiate withdrawal. Microinjections of alpha(h)CRH(9-41) into the central nucleus of the amygdala also reduced the severity of withdrawal whereas bed nucleus of the stria terminalis microinjections of alpha(h)CRH(9-41) were without effect. These experiments provide evidence for a role of amygdala, but not bed nucleus of the stria terminalis, CRH in opiate dependence. We propose a specific role for down-regulation of opiate receptor signaling in increased expression of the CRH gene in the amygdala. Moreover, we suggest that the roles accorded to CRH in the bed nucleus of the stria terminalis versus amygdala in coordinating responses to stressors may need to be reconsidered to distinguish between external and internal/interoceptive stressors.

Rationale: Pavlovian conditioning processes have been accorded an important role in maintaining persistent opiate administration. At least one locus for this contribution is during opiate withdrawal. These experiments studied the contribution of Pavlovian conditioning processes to morphine withdrawal., Objectives: To determine whether exposure to a distinctive context or odor paired with morphine withdrawal would provoke a withdrawal syndrome, defensive behaviors (e.g., freezing) and pain modulatory (e.g., hypoalgesia) responses similar to those produced by exposure to stimuli signaling other sources of aversive stimulation (e.g., footshock), or whether both withdrawal and fear-like responses would be provoked., Methods: Rats were used in four experiments to study the effects on defensive behavior and pain sensitivity of naloxone-precipitated morphine withdrawal or exposure to a distinctive context or odor previously paired with such withdrawal., Results: Injection of 2.5 mg/kg naloxone in morphine-dependent rats precipitated a withdrawal syndrome characterized by whole body shaking, diarrhea, ptosis, and postural abnormalities (experiment 1). Exposure to either a distinctive context (experiment 2) or odor (experiments 3) previously paired with morphine withdrawal provoked the species-typical defense response of freezing but not signs of withdrawal. Exposure to an odor previously paired with morphine withdrawal also provoked hypoalgesia in the formalin test, which was mediated by activity at opioid receptors (experiment 4)., Conclusions: These results show that opiate withdrawal supports the conditioning of defensive and hypoalgesic responses consistent with the arousal of a fear motivational system. The emergence of fear in these experiments, and the relationship between the freezing observed here and the learned avoidance and suppression observed in other withdrawal conditioning preparations, is discussed with reference to dual representation accounts of Pavlovian conditioning.

Rationale: Pairings of a sweet taste and injection of morphine result in a learned avoidance of that taste and learned analgesic tolerance. This avoidance is mediated by the drug's peripheral effect, while learned tolerance involves activation of N-methyl-D-aspartate (NMDA) receptors. Exposure to a sweet taste also reduces morphine analgesia. We studied whether this taste-mediated reduction was reversed by an NMDA or peripheral opioid receptor antagonist., Objectives: To determine whether an intraoral infusion of saccharin would modulate morphine analgesia in rats, and to study the contribution of NMDA as well as peripheral opioid receptors to this modulation., Methods: Six experiments used the rat's tail-flick response to study the effect of an intraoral infusion of a sodium saccharin solution on morphine analgesia, and the effects of the quaternary opioid receptor antagonist methylnaltrexone as well as the noncompetitive NMDA receptor antagonist MK-801 on this modulation of analgesia., Results: An intraoral infusion of saccharin reduced the analgesic effects of an intraperitoneal (i.p.) injection of morphine across a range of doses (experiment la), which was not attributable to an influence on tail-skin temperature (experiment 1b). This reduction was mediated by opioid receptors in the periphery and activation of NMDA receptors because morphine analgesia was reinstated by an i.p. injection of either methylnaltrexone (experiment 2a) or MK-801 (experiment 3a), which was not due to the effect of methylnaltrexone (experiment 2b) or MK-801 (experiment 3b) on morphine analgesia in the absence of saccharin., Conclusions: These results document evidence for an antagonism of morphine analgesia by actions of the drug at peripheral opioid receptors and excitatory amino-acid activity at NMDA receptors. They are discussed with reference to the aversive motivational effects of peripheral opioid receptors and pain facilitatory circuits.

Sensitivity to noxious stimulation is not invariant; rather, it is modulated by discrete pain inhibitory and facilitatory circuits. This paper reviews the neural circuits for pain facilitation, describes the conditions governing their environmental activation, and examines their role in an animal's behavioral repertoire. Mechanisms for pain facilitation are contrasted at both the neural and behavioral level with mechanisms for pain inhibition. In addition, the involvement of mechanisms for pain facilitation in morphine analgesic tolerance is discussed, and the implications of this involvement for accounts of the role of associative processes in analgesic tolerance are highlighted.

A flavor paired with morphine shifted to the right the function relating morphine dose to tail-flick latencies and provoked hyperalgesic responses when rats were tested in the absence of morphine. These learned increases in nociceptive sensitivity were not mediated by alterations in tail-skin temperature. Microinjection of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP-5) into the lateral ventricle reversed the hyperalgesic responses but spared the tolerance to morphine analgesia. By contrast, systemic administration of the noncompetitive NMDA receptor antagonist MK-801 or intrathecal infusion of AP-5 reversed the hyperalgesic responses as well as the tolerance to morphine analgesia. The results demonstrate that associatively mediated tolerance to morphine analgesia can co-occur with hyperalgesic responses and are discussed relative to learned activation of endogenous pronociceptive mechanisms.

Abstract Rationale: Pairings of a sweet taste and injection of morphine result in a learned avoidance of that taste and learned analgesic tolerance. This avoidance is mediated by the drug's peripheral effect, while learned tolerance involves activation of N-methyl-D-aspartate (NMDA) receptors. Exposure to a sweet taste also reduces morphine analgesia. We studied whether this taste-mediated reduction was reversed by an NMDA or peripheral opioid receptor antagonist. Objectives: To determine whether an intraoral infusion of saccharin would modulate morphine analgesia in rats, and to study the contribution of NMDA as well as peripheral opioid receptors to this modulation. Methods: Six experiments used the rat's tail-flick response to study the effect of an intraoral infusion of a sodium saccharin solution on morphine analgesia, and the effects of the quaternary opioid receptor antagonist methylnaltrexone as well as the noncompetitive NMDA receptor antagonist MK-801 on this modulation of analgesia. Results: An intraoral infusion of saccharin reduced the analgesic effects of an intraperitoneal (i.p.) injection of morphine across a range of doses (experiment 1a), which was not attributable to an influence on tail-skin temperature (experiment 1b). This reduction was mediated by opioid receptors in the periphery and activation of NMDA receptors because morphine analgesia was reinstated by an i.p. injection of either methylnaltrexone (experiment 2a) or MK-801 (experiment 3a), which was not due to the effect of methylnaltrexone (experiment 2b) or MK-801 (experiment 3b) on morphine analgesia in the absence of saccharin. Conclusions: These results document evidence for an antagonism of morphine analgesia by actions of the drug at peripheral opioid receptors and excitatory amino-acid activity at NMDA receptors. They are discussed with reference to the aversive motivational effects of peripheral opioid... [ABSTRACT FROM AUTHOR]