5-HT2A receptor subtype in the peripheral branch of sensory fibers is involved in the potentiation of inflammatory pain in rats

Abstract

One of the major serotonin (5-HT) receptor subtypes expressed in the rat dorsal root ganglion (DRG) neurons is the 5-HT2A receptor. We have previously shown that 5-HT2A receptors in the peripheral sensory terminals are responsible for 5-HT-induced pain and hyperalgesia. In the present study, we characterized neurons expressing 5-HT2A receptors in the rat DRG neurons by means of in situ hybridization, immunohistochemistry, reverse transcription-polymerase chain reaction (RT-PCR) and behavioral tests. In situ hybridization on consecutive sections revealed that 5-HT2A receptor mRNA is colocalized with calcitonin-gene related peptide (CGRP) mRNA (100/104; 96.2%) but not with c-Ret mRNA (1/115; 0.9%). Signals for 5-HT2A receptor mRNA were found in 9.4±2.2% of normal DRG (L5) neurons, most of which were small to medium in size. Four days of complete Freund's adjuvant-induced inflammation of the hindpaw doubled the incidence of 5-HT2A receptor mRNA-expressing neurons to 19.3±2.8%. The level of 5-HT2A receptor mRNA in DRGs of normal and various pathological conditions was then determined by RT-PCR. The level was up-regulated by peripheral inflammation, but not by axotomy or chronic constriction of the peripheral nerve. Systemic administration of 5-HT2A receptor antagonist (Sarpogrelate HCI) produced analgesic effects on thermal hyperalgesia caused by peripheral inflammation, but failed to attenuate thermal hyperalgesia in chronic constriction injury model. These findings suggest that 5-HT2A receptors are mainly expressed in CGRP-synthesizing small DRG neurons and may be involved in the potentiation of inflammatory pain in the periphery.