THE 15-LIPOXYGENASE PRODUCT, 8R, 15S-DIHETE, STEREOSPECIFICALLY SENSITIZES C-FIBER MECHANOHEAT NOCICEPTORS IN HAIRY SKIN OF RAT

1. This study examined the effects of the 15-lipoxygenase product of arachidonic acid metabolism, (8R, 15S)-dihydroxyicosa-(5E-9, 11, 13Z)tetraenoic acid (8R, 15S-diHETE) on mechanical threholds and thermal responses of saphenous nerve cutaneous C-fiber nociceptors that innervate the hairy skin of the rat hindpaw. Single C-fiber mechanoheat nociceptors (C-MH) that had von Frey hair (VFH) thresholds >5 g and were activated by a noxious heat stimulus were chosen for study. We also studied the effects of protaglandin E2 (PGE2), a cyclooxygenase product of arachidonic acid metabolism on these nociceptors. 2. The 63 C-MHs studied had a conduction velocity of 0.82 ± 0.03 m/s (mean ± SE) and a mechanical threshold of 13.4 ± 2.4 g. In a subgroup of these (n = 24), the thermal threshold was measured as (44 ± 1°C) (mean ± SE). 3. 8R, 15S-diHETE produced a significant decrease in mechanical threshold of C-MHs (n = 33). The 8R, 15S-diHETE-induced sensitization of C-MHs to mechanical stimuli was completely antagonized by coadministration with a stereoisomer, 8S, 15S-diHETE (n = 10). 4. The mechanical threshold of C-MHs (n = 10), previously injected with the combination of 8R, 15S-diHETE and 8S, 15S-diHETE, was significantly reduced by a subsequent injection of PGE2. In a separate group of C-MHs (n = 7), PGE2 was co-injected with 8S, 15S-diHETE, which failed to antagonize the sensitizing effect of PGE2 on mechanical threshold. 5. 8R, 15S-diHETE also sensitized C-MHs (n = 9) to a thermal stimulus consisting of 37°C for 5 min. After an injection of 8R, 15S-diHETE, the total number of spikes increased, compared with base-line and saline controls. 6. In conclusion, 8R, 15S-diHETE sensitizes nociceptors in the hairy skin of the rat to mechanical and thermal stimuli. The effect of 8R, 15S-diHETE on mechanical thresholds can be selectively antagonized by a stereoisomer, 8S, 15S-diHETE. This suggests that 8R, 15S-diHETE sensitizes cutaneous nociceptors by interacting with a stereospecific binding site. The data support the hypothesis that 8R, 15S-diHETE contributes to nonsteroidal anti-inflammatory agent (NSAIA)-resistant hyperalgesia.