Tolerance to the antinociceptive properties of morphine in the rat spinal cord: alteration of calcitonin gene-related peptide-like immunostaining and receptor binding sites.

Tolerance to the spinal antinociceptive effects of morphine develops rapidly after its chronic administration. The mechanism involved in this phenomenon is unclear, but it is unlikely due to a direct regulation of spinal opioid peptides and their receptor binding sites. A variety of neuropeptides, especially the neurokinins and calcitonin gene-related peptide (CGRP) are concentrated in primary sensory afferents and have thus been proposed to play significant roles in spinal nociceptive mechanisms. However, their functions in the development of tolerance to the antinociceptive properties of morphine have not been explored fully. We therefore investigated the possible involvement of various sensory neuropeptides including CGRP, substance P, galanin, neurotensin and neuropeptide Y and their receptors in the dorsal horn of the spinal cord during the development of tolerance to the antinociceptive action of intrathecal morphine. Morphine sulfate (7.5 micrograms/microliters/hr) was administered continuously at lumbar level L4 using mini-osmotic pumps for 3, 5, 7 and 14 days. Tolerance to the antinociceptive effect of morphine was verified with the tail-immersion test and became evident on the 5th day of treatment. In tolerant animals, there was a marked increase in CGRP-like immunostaining and a decrease (30-45%) in [125I]human CGRP alpha binding in laminae I, II and III of the dorsal horn of the spinal cord. These changes coincided with the onset of morphine tolerance and persisted for the 14-day period during which tolerance was present. Similar changes were not observed in the immunostaining or binding of the other neuropeptides studied.(ABSTRACT TRUNCATED AT 250 WORDS)