Investigation of the effects of oxytocin-induced increase in alpha-2 adrenoceptor sensitivity and pain threshold on the development of morphine dependence and tolerance in rats

It has been suggested that the increase in the nociceptive threshold, decrease in the blood pressure and corticosterone levels after repeated treatment with oxytocin have been suggested to depend on an increase in the synthesis and release of endogenous opioids and/or alpha-2 adrenoceptor responsiveness in rats. The secondary effects of oxytocin may affect the development of dependence and tolerance to morphine, since noradrenergic activity increases in the locus coeruleus in morphine dependence and alpha-2 agonists decrease withdrawal signs and tolerance to the analgesic effects. In the present study, development of tolerance to the analgesic and hypothermic effects, naloxone-induced withdrawal and response to clonidine in nociceptive threshold, body temperature and withdrawal signs were assessed in rats implanted with naloxone or morphine pellets following 5 days s.c. saline (control) or 1 mg/kg oxytocin (oxytocin) administrations. One day after the last dose, weight loss and increase in paw withdrawal latency was measured in oxytocin given animals. Analgesia and hyperthermia with time-dependent attenuation exhibited in the control-morphine and oxytocin-morphine groups 4, 24, and 48 h after pelleting. Morphine challenge demonstrated development of tolerance to the analgesic effect in the hot plate test in the control-morphine, and in the hot plate and tail immersion tests in the oxytocin-morphine groups. Tolerance was marked in the analgesic and hyperthermic effects and withdrawal was less in the oxytocin-morphine group. Clonidine potentiated jumping during withdrawal in the control-morphine and oxytocin-morphine groups and increased nociceptive threshold in the tail immersion test and decreased body temperature in the oxytocin-placebo group. The results supported the claims and findings that opioidergic activity and/or alpha-2 adrenoceptor sensitivity increases in oxytocin given animals However, the potentiation of tolerance development and the absence of marked differences in response to clonidine in the withdrawal signs indicated that further studies are required to evaluate the effects of repeated oxytocin administration related changes on morphine dependence and tolerance. Key Words: oxytocin, morphine dependence, clonidine, tolerance, analgesia