ALTERATION OF CALCITONIN-GENE-RELATED PEPTIDE AND ITS RECEPTOR-BINDING SITES DURING THE DEVELOPMENT OF TOLERANCE TO MU-OPIOID AND DELTA OPIOID

Calcitonin gene related peptide (CGRP), one of the most abundant peptides in the spinal cord, is localized in primary afferents and released following nociceptive stimuli. Its colocalization and corelease with substance P, a well-known nociceptive neuropeptide, support the importance of CORP in pain mechanisms. However, its distinctive function in that regard remains to be fully established. Recently, we reported that increases in CGRP-like immunostaining and decrements in specific I-125-labelled human CGRP alpha([I-125]hCGRP alpha) binding sites in the spinal cord were correlated with the development of tolerance to the spinal antinociceptive action of a Ir, opioid agonist, morphine. The goal of the present study was to investigate whether the development of tolerance to other classes of opioids, namely, delta and kappa agonists, can also alter CORP-like immunostaining and receptors in the rat spinal cord. The antinociceptive effects of ail opioids were monitored by the tail-immersion test. Tolerance to their antinociceptive properties was induced by the infusion for 7 days of mu (morphine sulfate, 7.5 mu g/h), delta ([D-Pen(2),D-Pen(5)]enkephalin (DPDPE), 2.0 mu g/h), and kappa (U-50488H, 10.0 mu g/h) related agonists at the spinal level (L(4)), using osmotic minipumps. We confirmed that rats chronically treated with morphine showed significant decreases in [I-125]CGRp alpha binding in laminae I, II, and III of the L(4) spinal cord, while CGRP-like immunostaining was increased in these same laminae. Similar effects were observed following a treatment with the delta agonist, DPDPE, while the kappa agonist, U-50488H, apparently only slightly decreased [I-125]CGRP alpha binding in lamina II. Binding in other laminae and CORP-like immunostaining were not affected. These results suggest a specific interaction between spinal CORP systems and the development of tolerance to the spinal antinociceptive effects of mu- and delta-related agonists.