Upregulation of pronociceptive mediators and downregulation of opioid peptide by adrenomedullin following chronic exposure to morphine in rats.

Adrenomedullin (AM) belongs to a calcitonin gene-related peptide (CGRP) family and has been demonstrated to recruit CGRP following chronic use of morphine and neuronal nitric oxide synthase (nNOS) in inflammation. The present study investigated the possibility that AM initiates the changes of other molecules contributing to the development of morphine tolerance in its chronic use. Intrathecal (i.t.) co-administration of the AM receptor antagonist AM22-52 (35.8 μg) inhibited tolerance to morphine-induced analgesia while a daily injection of the AM receptor agonist AM1-50 (8 μg, i.t., bolus) for 9 days induced a decrease in the potency of morphine analgesia and thermal hyperalgesia. Persistent exposure of cultured dorsal root ganglion (DRG) explants to morphine (3.3 μM) for 4 days resulted in an increase in AM and CGRP mRNA levels. However, morphine failed to produce these effects in the presence of AM22-52 (2 μM). The i.t. administration of morphine for 6 days increased the expression of nNOS in the spinal dorsal horn and DRG neurons but decreased expression of the endogenous opioid peptide bovine adrenal medulla 22 (BAM22) in small- and medium-sized neurons in DRG. Particularly, the co-administration of AM22-52 (35.8 μg) inhibited the morphine-induced alterations in nNOS and BAM22. These results indicated that the increase in nNOS and CGRP expressions and the decrease in BAM22 were attributed to the increased AM receptor signaling induced by chronic morphine. The present study supports the hypothesis that the enhancement of AM bioactivity triggered upregulation of pronociceptive mediators and downregulation of pain-inhibiting molecule in a cascade contributing to the development of morphine tolerance.