Endomorphins and activation of the hypothalamo-pituitary-adrenal axis

Endomorphin (EM)-1 and EM-2 are opioid tetrapeptides recently located in th e central nervous system and immune tissues with high selectivity and affin ity for the mu -opioid receptor. Intracerebroventricular (i.c.v.) administr ation of morphine stimulates the hypothalamo-pituitary-adrenal (HPA) axis. The present study investigated the effect of centrally administered EM-1 an d EM-2 on HPA axis activation. Rats received a single i.c.v. injection of e ither EM-1 (0.1, 1.0, 10 mug), EM-2 (10 mug), morphine (10 mug), or vehicle (0.9% saline). Blood samples for plasma corticosterone determinations were taken immediately prior to i.c.v. administration and at various time point s up to 4 h post-injection. Trunk blood, brains and pituitaries were collec ted at 4 h. Intracerebroventricular morphine increased plasma corticosteron e levels within 30 min, whereas EM-1 and EM-2 were without effect. In addit ion, pre-treatment of i.c.v. EM-1 did not block the rise in corticosterone after morphine. Corticotrophin-releasing factor (CRF) mRNA and arginine vas opressin (AVP) mRNA in the paraventricular nucleus (PVN) and POMC mRNA in t he anterior pituitary were found to be unaffected by tither morphine or end omorphins. Since release of other opioids are elevated in response to acute stress, we exposed rats to a range of stressors to determine whether plasm a EM-1 and EM-2 can be stimulated by HPA axis activation. Plasma corticoste rone, ACTH and beta -endorphin were elevated following acute restraint stre ss, but concentrations of plasma EM-1-immunoreactivity (ir) and EM-2-ir did not change significantly. Corticosterone, ACTH and beta -endorphin were fu rther elevated in adjuvant-induced arthritis (AA) rats by a single injectio n of lipopolysaccharide (LPS), but not by restraint stress. In conclusion, neither EM-1 or EM-2 appear to influence the regulation of the HPA axis. Th ese data suggest that endomorphins may be acting on a different subset of t he Ct-opioid receptor than morphine. The failure to induce changes in plasm a EM-ir in response to the chronic inflammatory stress of AA, the acute imm unological stress of LPS, or the psychological stress of restraint, argues against an important role for endomorphins in mediating HPA axis activity.