A CB(2) receptor agonist, A-836339, modulates wide dynamic range neuronal activity in neuropathic rats: contributions of spinal and peripheral CB(2) receptors.
We investigated the systemic and site-specific actions of a selective CB(2) receptor agonist, A-836339 on mechanically evoked (10 g von Frey hair) and spontaneous firing of spinal wide dynamic range (WDR) neurons in neuropathic (L5 and L6 ligations) and sham rats. Systemic administration of A-836339 (0.3-3 micromol/kg, i.v.) reduced both evoked and spontaneous WDR neuronal activity in neuropathic, but not sham rats. The effects in neuropathic rats were blocked by pre-administration of a CB(2), but not a CB(1), receptor antagonist. Similar to systemic delivery, intra-spinal injection of A-836339 (0.3 and 1 nmol) also attenuated both von Frey-evoked and spontaneous firing of WDR neurons in neuropathic rats. Intra-spinal injections of A-836339 were ineffective in sham rats. Application of A-836339 (3-30 nmol) onto the ipsilateral L5 dorsal root ganglion (DRG) of neuropathic rats reduced the von Frey-evoked activity of WDR neurons, but spontaneous firing was unaltered. All effects of A-836339 on WDR neuronal activity following either intra-spinal or intra-DRG administration were blocked by pre-administration of a CB(2) receptor antagonist. Pre-administration of a CB(1) receptor antagonist did not alter the site-specific effects of A-836339. Injection of A-836339 (300 nmol) into the neuronal receptive field on the ipsilateral hind paw did not affect evoked or spontaneous firing of WDR neurons. Thus, the current data demonstrate that modulation of spinal neuronal activity by a CB(2) receptor agonist is enhanced following peripheral nerve injury, and further delineate the contribution of spinal and peripheral CB(2) receptors to this modulation.
McGaraughty
S
S
Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6118, USA. Steve.P.McGaraughty@abbott.com
Chu
K L
KL
Dart
M J
MJ
Yao
B B
BB
Meyer
M D
MD
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001892:Camphanes / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D005727:Ganglia, Spinal / Q000473:pathology*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D010523:Peripheral Nervous System Diseases / Q000473:pathology*; D010812:Physical Stimulation / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000502:physiology; D000077285:Rimonabant; D013116:Spinal Cord / Q000473:pathology*; D013844:Thiazoles / Q000494:pharmacology
C540311:A-836339; D001892:Camphanes; D010880:Piperidines; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; D013844:Thiazoles; D000077285:Rimonabant