DIFFERENTIATION OF SPINAL AND SUPRASPINAL OPIOID RECEPTORS BY MORPHINE-TOLERANCE

Mice treated for 72hrs with morphine (subcutaneously implanted pellets) were tested with a variety of opioid receptor agonists to examine the development of tolerance and cross-tolerance to their analgesic action. The development of spinal and supraspinal tolerance following morphine treatment was evaluated by administering compounds systematically (sc), intrathecally (IT) and intracerebroventicularly (ICV). Following morphine treatment, tolerance to morphine analgesia was observed following IT, ICV and sc administration. Chronic morphine treatment also produced cross-tolerance to the analgesic effects of the selective δ opioid receptor agonist [D-Pen2, D-Pen5]enkephalin (DPDPE) following IT and ICV administration. However, morphine treatment selectively produced cross-tolerance to ICV [D-Ala2, NMePhe4, Gly-ol5]enkephalin (DAGO) (μ receptor agonist) analgesia, without altering IT DAGO analgesia. These results suggest that brain and spinal cord receptors mediating the effects of DAGO differ in terms of the development of cross-tolerance to morphine; and suggest that tolerance to systemic morphine may be due to changes in spinal δ and brain μ and δ receptor mechanisms. © 1990.