No abstract

Antagonists of the NOP receptor have antidepressant effects in rodent models, suggesting that the N/OFQ-NOP system may play an important role in affective disorders. Furthermore, multiple lines of experimental evidence link N/OFQ neurotransmission with physiological and behavioral responses to stress. One possibility is that disregulated expression of the N/OFQ peptide neurotransmitter and/or the NOP receptor may participate in the etiology of stress-induced psychopathology. In the present set of experiments, we compared gene expression for prepro-N/OFQ and NOP receptor in groups of rats that were exposed to differing regimens of social defeat stress. Male Long-Evans rats were exposed to no social defeat, a single, acute social defeat or to repeated social defeats with or without an acute defeat on the final day. In situ hybridization was conducted with 35S-labelled riboprobes aimed at prepro-N/OFQ mRNA or NOP receptor mRNA. Expression was analyzed by quantification of optical density in limbic and extra-limbic forebrain regions. There were no statistically significant changes in prepro-N/OFQ mRNA expression after stress exposure in any of the brain regions analyzed. However, the rats that were exposed to acute social defeat displayed elevations in NOP receptor mRNA expression in the central and basomedial nuclei of the amygdala and in the paraventricular nucleus of the hypothalamus. Additionally, the rats that were acutely stressed after a history of repeated social defeat also displayed elevated levels of NOP receptor mRNA expression in the paraventricular nucleus of the hypothalamus. These results suggest that the N/OFQ-NOP receptor system is affected by acute stress exposure, particularly in limbic regions. This stress-induced upregulation of NOP receptor gene expression further supports the possibility that disregulation of the N/OFQ-NOP system may contribute to behavioral and hormonal disregulation following stress.

Higher-order processing of nociceptive input is distributed in corticolimbic regions of the brain, including the anterior cingulate, parieto-insular and prefrontal cortices, as well as subcortical structures such as the bed nucleus of stria terminalis and amygdala. In addition to their role in pain processing, these regions encode or modulate emotional, motivational and sensory responses to stress. Thus, pain and stress pathways in the brain intersect at cortical and subcortical forebrain structures. Accordingly, previous work has shown that acute restraint stress in female rats induces heat hyperalgesia in a forebrain-dependent operant test of thermal escape. In the present study, we investigated the effects of social defeat stress in male rats on the operant escape task, as well as in a test of nociceptive thermal preference. After establishing baseline behaviors in these tests, separate groups of rats were socially defeated by dominant “resident” male rats. They were tested for thermal preference after 5 successive social defeat sessions. Escape from cold, heat and a neutral warm temperature also was evaluated after social defeat. Defeated rats exhibited a significant increase in cold preference after social defeat compared to the baseline. In the escape task, the rats exhibited increased escape from warm and nociceptive cold and heat temperatures. Thus, chronic social stress produces hyperalgesia for both hot and cold stimuli in male rats, suggesting a mutually facilitatory cross-regulation between central pathways regulating stress and pain.