Potentiation of Clonidine Analgesia in Rats Deleted of TRPV1‐Expressing Afferent Neurons

Abstract

The α2-adrenergic receptors (α2-ARs) are located on primary afferent terminals and on neurons in the spinal cord dorsal horn. However, their role in the analgesic effect produced by the α2-AR agonist is not known. In this study, we determined whether removal of presynaptic α2-ARs on TRPV1-expressing sensory neurons by resiniferatoxin (RTX) alters the antinociceptive effect of the α2-AR agonist clonidine. 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 α2A-AR-immunoreactivity co-expressed with TRPV1-expressing terminals in the spinal cord was eliminated. However, the α2C-AR-immunoreactivity in the spinal cord was little changed. Surprisingly, intrathecal 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. In the vehicle-treated group, although intrathecal clonidine produced a large increase in the thermal withdrawal latency, it only had a small and short-lasting effect on the mechanical withdrawal threshold. Furthermore, the protein kinase Cγ-immunoreactivity in the superficial dorsal horn was profoundly decreased in RTX-treated rats. This study provides new information that the antinociceptive effect of spinally administered α2-AR agonists is largely modality-specific. Loss of TRPV1-expressing sensory neurons leads to a reduction in presynaptic α2A-ARs but paradoxically potentiates the effect of clonidine on mechano-nociception, possibly by reducing α2-AR desensitization through protein kinase Cγ.