P2X₃ Receptor Mediates Heat Hyperalgesia in a Rat Model of Trigeminal Neuropathic Pain

Abstract 

The present study was undertaken to determine the role of P2X₃ receptor (P2X₃R) on heat hyperalgesia in a newly developed rat model of trigeminal neuropathic pain. The unilateral infraorbital nerve (IoN) was partially ligated by 6-0 silk. To assess heat sensitivity, a vibrissal pad (VP) was placed on a hot plate and the latency until the rats withdrew their head was measured. Mechanical sensitivity of VP was also assessed by the use of von Frey filament. Both heat and mechanical hyperalgesia were observed at the VP ipsilateral to the IoN ligation. The latency to heat stimuli was prolonged after subcutaneous administration of pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS, P2X_{1,2,3,5,7,1/5,2/3}R antagonist) and 2′,3′-O-(2,4,6-trinitrophenyl) adenosine 5′-triphosphate (TNP-ATP, P2X_1,3,2/3,1/5R antagonist). The latency was shortened after administration of α,β-methylene ATP (α,β-meATP, P2X_1,3,2/3R agonist), although no changes appeared after administration of β,γ-methylene-L-ATP (β,γ-me-L-ATP, P2X₁R agonist). The protein gene product-9.5 and calcitonin gene-related peptide immunoreactive nerve fibers significantly decreased in the VP skin of ipsilateral to the IoN ligation. In the ipsilateral trigeminal ganglion, the number of P2X₃-immunoreactive neurons significantly increased in the small cell group. In this study, we developed an experimental model of trigeminal neuropathic pain by partial ligation of IoN, which produced heat and mechanical hyperalgesia in the VP. Pharmacological and immunohistochemical studies revealed that the P2X₃R plays an important role in the heat hyperalgesia observed in this model.

Perspective

The study describes the development of a novel model of trigeminal neuropathic pain. Heat hyperalgesia in this model was inhibited by peripheral injection of P2XR antagonists. The results suggest that P2X₃R is a potential target for development of a novel therapy for trigeminal neuropathic pain.

Key words: P2X₃, heat hyperalgesia, trigeminal neuropathic pain, PGP9.5, CGRP