Inhibition of transient receptor potential vanilloid type 1 through α(2) adrenergic receptors at peripheral nerve terminals relieves pain

The activation of α(2) adrenergic receptors contributes to analgesia not only in the central nervous system but also in the peripheral nervous system. We reported that noradrenaline inhibits the activity of transient receptor potential vanilloid 1 (TRPV1) evoked by capsaicin through α(2) receptors in cultured rat dorsal root ganglion (DRG) neurons. However, it is unclear whether activation of TRPV1 expressed in peripheral nerve terminals is inhibited by α(2) receptors and whether this phenomenon contributes to analgesia. Therefore, we examined effects of clonidine, an α(2) receptor agonist, on several types of nociceptive behaviors, which may be caused by TRPV1 activity, and subtypes of α(2) receptors expressed with TRPV1 in primary sensory neurons in rats. Capsaicin injected into hind paws evoked nociceptive behaviors and clonidine preinjected into the same site inhibited capsaicin-evoked responses. This inhibition was not observed when clonidine was injected into the contralateral hind paws. Preinjection of clonidine into the plantar surface of ipsilateral, but not contralateral, hind paws reduced the sensitivity to heat stimuli. Clonidine partially reduced formalin-evoked responses when it was preinjected into ipsilateral hind paws. The expression level of α(2C) receptor mRNA quantified by real-time PCR was highest followed by those of α(2A) and α(2B) receptors in DRGs. α(2A) and α(2C) receptor-like immunoreactivities were detected with TRPV1-like immunoreactivities in the same neurons. These results suggest that TRPV1 and α(2) receptors are coexpressed in peripheral nerve terminals and that the functional association between these two molecules causes analgesia.