Potentiation of spinal alpha(2)-adrenoceptor analgesia in rats deficient in TRPV1-expressing afferent neurons.
The alpha(2)-adrenoceptors (alpha(2)-ARs) are located on primary afferent terminals and on neurons in the spinal cord dorsal horn. However, their relative contribution to the analgesic effect of the alpha(2)-AR agonists is not known. In this study, we determined the role of certain presynaptic alpha(2)-ARs in the antinociceptive effect produced by intrathecal administration of the alpha(2)-AR agonist clonidine. TRPV1-expressing sensory neurons were removed by resiniferatoxin (RTX). The effect of intrathecal injection of clonidine was measured by testing the paw withdrawal response to noxious mechanical or heat stimuli. In RTX-treated rats, the alpha(2A)-AR-immunoreactivity co-expressed with TRPV1-expressing terminals in the spinal cord was eliminated. However, the alpha(2C)-AR-immunoreactivity in the spinal cord was little changed. Surprisingly, intrathecal administration of clonidine produced a much greater increase in the mechanical withdrawal threshold in RTX- than in vehicle-treated rats. The duration of the clonidine effect was also significantly increased in RTX-treated rats. Furthermore, in the vehicle-treated group, although intrathecal injection of clonidine produced a large increase in the thermal withdrawal latency, it only had a small and short-lasting effect on the mechanical withdrawal threshold. This study provides new information that the antinociceptive effect of spinally administered alpha(2)-AR agonists is largely modality-specific. Loss of TRPV1-expressing sensory neurons leads to a reduction in presynaptic alpha(2A)-ARs but paradoxically potentiates the effect of clonidine on mechano-nociception.
Chen
Shao-Rui
SR
Department of Anesthesiology and Pain Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Pan
Hao-Min
HM
Richardson
Timothy E
TE
Pan
Hui-Lin
HL
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D008297:Male; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D010147:Pain Measurement / Q000187:drug effects*; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology*; D050916:TRPV Cation Channels / Q000378:metabolism*; D013997:Time Factors
D000316:Adrenergic alpha-Agonists; D018341:Receptors, Adrenergic, alpha-2; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D003000:Clonidine