Characterization of a Model of Chronic Orofacial Hyperalgesia in the Rat: Contribution of NA_V 1.8

Abstract 

The purpose of this study was to develop and characterize a model of orofacial inflammatory hyperalgesia. Injection of complete Freund's adjuvant (CFA) into the upper lip/whisker pad of the rat produced significant and long-lasting thermal (≥14 days) and mechanical (≥28 days) hyperalgesia in the area of CFA injection. Both indomethacin and morphine, given systemically, significantly attenuated thermal hyperalgesia; the effect of morphine was shown to be opioid receptor-mediated. We also examined the contribution of the tetrodotoxin-resistant voltage-gated sodium channel Na_v1.8 in CFA-produced orofacial mechanical hypersensitivity. Na_v1.8 mRNA was increased ≥2.5-fold in trigeminal ganglion neurons 1 and 2 weeks after CFA treatment, and Na_v1.8 protein was increased in the infraorbital nerve over a similar time course. The changes observed were time-dependent and had returned to baseline when examined 2 months after inflammation; there were no changes in Na_v1.9 mRNA in trigeminal ganglion neurons after CFA treatment. In support of this, Na_v1.8 antisense oligodeoxynucleotide treatment significantly attenuated CFA-produced mechanical hypersensitivity. These results document development of a model of inflammatory orofacial hyperalgesia, which, consistent with other reports, indicate a contribution of tetrodotoxin-resistant, voltage-gated sodium channel Na_v1.8.

Perspective

Orofacial hypersensitivity develops postoperatively as a routine course of orofacial surgery, and mechanical allodynia is characteristic of temporomandibular joint disorder. The results described in this report are novel with respect to the duration of orofacial hypersensitivity produced and suggest that pharmacological targeting of the voltage-gated sodium channel Na_v1.8 may be useful in managing hypersensitivity.

Key words: Orofacial pain, sodium channels, thermal hyperalgesia, mechanical hyperalgesia, orofacial pain model