Central and peripheral sites of action for CB₂ receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats.
OBJECTIVE
Cannabinoid CB₂ receptor activation by selective agonists has been shown to produce analgesic effects in preclinical models of inflammatory and neuropathic pain. However, mechanisms underlying CB₂-mediated analgesic effects remain largely unknown. The present study was conducted to elucidate the CB₂ receptor expression in 'pain relevant' tissues and the potential sites of action of CB₂ agonism in rats.


METHODS
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 CB₂ mediated antinociception were evaluated in vivo following intra-DRG, intrathecal (i.t.) or intraplantar (i.paw) administration of potent CB₂-selective agonists A-836339 and AM1241.


RESULTS
CB₂ 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 CB₂ 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
These results demonstrate that both DRG and spinal cord are important sites contributing to CB₂ receptor-mediated analgesia and that the changes in CB₂ receptor expression play a crucial role for the sites of action in regulating pain perception.
Hsieh
Gin C
GC
Global Pharmaceutical Research & Development, Abbott Laboratories, Abbott Park, IL 60064, USA. gin.c.hsieh@abbott.com
Pai
Madhavi
M
Chandran
Prasant
P
Hooker
Bradley A
BA
Zhu
Chang Z
CZ
Salyers
Anita K
AK
Wensink
Erica J
EJ
Zhan
CenChen
C
Carroll
William A
WA
Dart
Michael J
MJ
Yao
Betty B
BB
Honore
Prisca
P
Meyer
Michael D
MD
D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy; D008297:Male; D009437:Neuralgia / Q000139:chemically induced / Q000188:drug therapy*; D018847:Opioid Peptides / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D058748:Pain Perception; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use
C540311:A-836339; C439263:AM 1241; D000700:Analgesics; D002186:Cannabinoids; D018847:Opioid Peptides; D012333:RNA, Messenger; D043885:Receptor, Cannabinoid, CB2; D013844:Thiazoles