Blockade of adrenomedullin receptors reverses morphine tolerance and its neurochemical mechanisms

Dongmei Wang, Peiwen Chen, Qi Li, Rémi Quirion, Yanguo Hong*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Adrenomedullin (AM) has been demonstrated to be involved in the development of opioid tolerance. The present study further investigated the role of AM in the maintenance of morphine tolerance, morphine-associated hyperalgesia and its cellular mechanisms. Intrathecal (i.t.) injection of morphine for 6 days induced a decline of its analgesic effect and hyperalgesia. Acute administration of the AM receptor antagonist AM22-52 resumed the potency of morphine in a dose-dependent manner (12, 35.8 and 71.5μg, i.t.). The AM22-52 treatment also suppressed morphine tolerance-associated hyperalgesia. Furthermore, i.t. administration of AM22-52 at a dose of 35.8μg reversed the morphine induced-enhancement of nNOS (neuronal nitric oxide synthase) and CGRP immunoreactivity in the spinal dorsal horn and/or dorsal root ganglia (DRG). Interestingly, chronic administration of morphine reduced the expression of the endogenous opioid peptide bovine adrenal medulla 22 (BAM22) in small- and medium-sized neurons in DRG and this reduction was partially reversed by the administration of AM22-52 (35.8μg). These results suggest that the activation of AM receptors was involved in the maintenance of morphine tolerance mediating by not only upregulation of the pronociceptive mediators, nNOS and CGRP but also the down-regulation of pain-inhibiting molecule BAM22. Our data support the hypothesis that the level of both pronociceptive mediators and endogenous pain-inhibiting molecules has an impact on the potency of morphine analgesia. Targeting AM receptors is a promising approach to maintain the potency of morphine analgesia during chronic use of this drug.

Original languageEnglish (US)
Pages (from-to)83-90
Number of pages8
JournalBehavioural Brain Research
Volume221
Issue number1
DOIs
StatePublished - Aug 1 2011
Externally publishedYes

Keywords

  • Adrenomedullin
  • Dorsal root ganglia (DRG)
  • Hyperalgesia
  • Morphine tolerance
  • Spinal cord

ASJC Scopus subject areas

  • Behavioral Neuroscience

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