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Acute stressors induce changes in numerous behavioral parameters through activation of the hypothalamic-pituitary-adrenal (HPA) axis. Several important hormones in paraventricular nucleus of the hypothalamus (PVN) play the roles in these stress-induced reactions. Corticotropin-releasing hormone (CRH), arginine-vasopressin (AVP) and corticosterone are considered as molecular markers for stress-induced grooming behavior. Oxytocin in PVN is an essential modulator for stress-induced antinociception. The clock gene,  Per1 , has been identified as an effecter response to the acute stresses, but its function in neuroendocrine stress systems remains unclear. In the present study we observed the alterations in grooming and nociceptive behaviors induced by acute immobilization stress in  Per1  mutant mice and other genotypes (wild types and  Per2  mutant). The results displayed that stress elicited a more robust effect on grooming behavior in  Per1  mutant mice than in other genotypes. Subsequently, the obvious stress-induced antinociception was observed in the wild-type and  Per2  mutant mice, however, in  Per1  mutant, this antinociceptive effects were partially-reversed (mechanical sensitivity), or over-reversed to hyperalgesia (thermal sensitivity). The real-time qPCR results showed that in PVN, there were stress-induced up-regulations of  Crh ,  Avp  and  c-fos  in all of genotypes; moreover, the expression change of  Crh  in  Per1  mutant mice was much larger than in others. Another hormonal gene,  Oxt , was up-regulated induced by stress in wild-type and  Per2  mutant but not in  Per1  mutant. In addition, the stress significantly elevated the serum corticosterone levels without genotype-dependent differences, and accordingly the glucocorticoid receptor gene,  Nr3c1 , expressed with a similar pattern in PVN of all strains. Taken together, the present study indicated that in acute stress treated  Per1  mutant mice, there are abnormal hormonal responses in PVN, correlating with the aberrant performance of stress-induced behaviors. Therefore, our findings suggest a novel functional role of  Per1  in neuroendocrine stress system, which further participates in analgesic regulation.

Deficiency of Antinociception and Excessive Grooming Induced by Acute Immobilization Stress in Per1 Mutant Mice