Premium
Central and peripheral sites of action for CB 2 receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats
Author(s) -
Hsieh Gin C,
Pai Madhavi,
Chandran Prasant,
Hooker Bradley A,
Zhu Chang Z,
Salyers Anita K,
Wensink Erica J,
Zhan CenChen,
Carroll William A,
Dart Michael J,
Yao Betty B,
Honore Prisca,
Meyer Michael D
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2010.01046.x
Subject(s) - neuropathic pain , medicine , analgesic , pharmacology , hyperalgesia , chronic pain , receptor , cannabinoid , spinal cord , cannabinoid receptor , in vivo , nociception , anesthesia , agonist , biology , microbiology and biotechnology , psychiatry
BACKGROUND AND PURPOSE Cannabinoid CB 2 receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory and neuropathic pain. However, mechanisms underlying CB 2 ‐mediated analgesic effects remain largely unknown. The present study was conducted to elucidate the CB 2 receptor expression in ‘pain relevant’ tissues and the potential sites of action of CB 2 agonism in rats. EXPERIMENTAL APPROACH Expression of cannabinoid receptor mRNA was evaluated by quantitative RT‐PCR in dorsal root ganglia (DRGs), spinal cords, paws and several brain regions of sham, chronic inflammatory pain (CFA) and neuropathic pain (spinal nerve ligation, SNL) rats. The sites of CB 2 mediated antinociception were evaluated in vivo following intra‐DRG, intrathecal (i.t.) or intraplantar (i.paw) administration of potent CB 2 ‐selective agonists A‐836339 and AM1241. KEY RESULTS CB 2 receptor gene expression was significantly up‐regulated in DRGs (SNL and CFA), spinal cords (SNL) or paws (CFA) ipsilateral to injury under inflammatory and neuropathic pain conditions. Systemic A‐836339 and AM1241 produced dose‐dependent efficacy in both inflammatory and neuropathic pain models. Local administration of CB 2 agonists also produced significant analgesic effects in SNL (intra‐DRG and i.t.) and CFA (intra‐DRG) pain models. In contrast to A‐836339, i.paw administration of AM‐1241 dose‐relatedly reversed the CFA‐induced thermal hyperalgesia, suggesting that different mechanisms may be contributing to its in vivo properties. CONCLUSIONS AND IMPLICATIONS These results demonstrate that both DRG and spinal cord are important sites contributing to CB 2 receptor‐mediated analgesia and that the changes in CB 2 receptor expression play a crucial role for the sites of action in regulating pain perception.