Characterization of Prostaglandin Receptors Mediating Sensitization of Trigeminal Nociceptors

Objectives: NSAIDS decrease pain by inhibiting prostaglandins (PG) synthesis. Despite widespread use of cyclooxygenase inhibitors for orofacial pain, little is known about PG sensitization or receptor expression in the trigeminal system. Southall and Vasko demonstrated that two PG receptors (EP receptors) mediate sensitization of dorsal root ganglia nociceptors. No study has identified the presence of EP receptors or their extent of co-localization with TRP V1 in the trigeminal ganglia. Consequently, sensitization of trigeminal nociceptors by PGE2 and identification of the receptors responsible for mediating this response was evaluated. Methods: To evaluate the effect of PGE2 on capsaicin-induced excitation of nociceptors, cultured trigeminal neurons were exposed to either PGE2 or vehicle for 15 minutes, and the amount of evoked immunoreactive calcitonin-gene-related peptide (iCGRP) was measured using radioimmunoassay. Next, full-length, DIG-labeled cRNA riboprobes against EP receptors 1-4 were constructed. Using the probes, in situ hybridization was carried out on rat trigeminal ganglia to determine the extent of respective mRNA expression; the sense strand was used as a negative control. Finally, the extent of co-localization with TRP V1 was evaluated using immunohistochemistry. Results: Increased iCGRP release indicated that PGE2 sensitizes trigeminal TRP V1 positive nociceptors. Furthermore, PG receptors, EP 2 and EP 3, were expressed in approximately 16% and 9% of native trigeminal neurons, respectively. Neither EP 1 nor EP 4 were expressed. The majority of EP 2 and EP 3 expressing cells were of medium diameter (nociceptive range) and demonstrated co-localization with TRP V1. Conclusion: PGE2 can sensitize noxious, heat-sensitive trigeminal nociceptors via activation of PG receptors, EP 2 and EP 3. Thus, specific EP receptors are potential targets for antagonists in the pharmacotherapeutic management of pain. Supported by NIDCR, T-32 Grant #DE14318 – CO STAR Program