Involvement of adrenomedullin in the pathogenesis of inflammatory pain and morphine tolerance / 生理学报

The increase of pronociceptive mediators in the dorsal root ganglia (DRG) and spinal dorsal horn is an important mechanism in the pathogenesis of inflammatory pain and opioid tolerance. Adrenomedullin (AM) belongs to calcitonin gene-related peptide (CGRP) family and has been recently demonstrated to be a pain-related peptide. It has also been shown that the expression and release of AM are increased in the DRG and spinal dorsal horn during inflammation and repeated use of morphine. Intrathecal administration of the selective AM receptor antagonist AM22-52 abolishes inflammatory pain and morphine tolerance, suggesting that enhanced AM receptor signaling in the DRG and spinal dorsal horn contributes to the induction of inflammatory pain and morphine tolerance. The present review highlights the recent developments regarding the involvement of AM in these two disorders. The neurological mechanisms of AM's actions are also discussed.

Effects of blockade of 5-HT2A receptors in inflammatory site on complete Freund's adjuvant-induced chronic hyperalgesia and neuropeptide Y expression in the spinal dorsal horn in rats / 生理学报

5-hydroxytryptamine (5-HT) released in inflammatory tissues plays a pivotal role in pain hypersensitivity. However, it is not clear whether 5-HT2A receptors in the inflamed tissues mediate this effect. The present study investigated the contribution of 5-HT2A receptors in the periphery to chronic inflammatory pain. Complete Freund's adjuvant (CFA) was injected subcutaneously in the hindpaw of rats. The selective 5-HT2A receptor antagonist ketanserin was given in the inflamed site. Paw withdrawal latency responding to heat or mechanical stimuli was measured. Expression of neuropeptide Y (NPY) in the spinal dorsal horn and dorsal root ganglia (DRG) was assayed using immunohistochemistry technique. The results showed that ketanserin administered in the inflamed site inhibited thermal hyperalgesia in a dose-dependent manner (20, 40 and 80 µg) induced by the intraplantar injection of CFA. Ketanserin given once per day at a dose of 80 µg abolished heat hyperalgesia and also attenuated mechanical allodynia on the third day. CFA injection increased the expression of NPY in superficial laminae of the spinal cord, but not in the DRG. The local treatment of ketanserin completely inhibited CFA-induced increase in NPY expression in superficial laminae of the spinal cord. These results indicated that activation of 5-HT2A receptors in the inflamed tissues was involved in the pathogenesis of inflammatory pain and the blockade of 5-HT2A receptors in the periphery could relieve pain hypersensitivity and normalize the cellular disorder in the spinal dorsal horn associated with pathological pain. The present study suggests that the peripheral 5-HT2A receptors can be a promising target for pharmaceutical therapy to treat chronic inflammatory pain without central nervous system side effects.