Bradykinin-induced nociceptor sensitisation to heat depends on cox-1 and cox-2 in isolated rat skin

Bradykinin is an important inflammatory mediator that can either activate and/or sensitise nociceptors to heat stimuli applied to the skin. Several studies have suggested that prostaglandins and thus the cyclooxygenase (cox) enzymes are important in the sensitisation process but little is known about the relative involvement of the two cox isoforms, cox-1 and cox-2. Extracellular recordings were made from C-mechanoheat-sensitive fibres in isolated rat skin-saphenous nerve preparations. Bradykinin-mediated sensitisation of heat responses in these afferents was significantly attenuated by the selective cox-1 inhibitor, SC-560, and by the selective cox-2 inhibitor, NS-398. In the same experiments, bradykinin-mediated induction of ongoing activity was reduced by SC-560 but not NS-398. In a second series of experiments, bradykinin-stimulated synthesis and release of prostaglandin E₂ (PGE₂) was measured in isolated skin-nerve preparations. Although the basal release of PGE₂ appeared unaffected by either drug, bradykinin-stimulated PGE₂ release from the skin was inhibited by both SC-560 and NS-398. Immunocytochemical evaluation revealed cox-1 immunostaining was present in large cutaneous nerve branches, small intradermal nerve bundles as well as nerve endings within the skin. Cox-1 labelling was also present in non-neuronal cell types such as mast cells. Cox-2 immunoreactivity was weak but where present was located in small nerve bundles, smaller intradermal nerve bundles and nerve endings. This study shows that both cox isoforms are present in skin and that they have an important role in mediating bradykinin-evoked heat sensitisation of C-MH sensitive fibres through cox-1 and cox-2 dependent prostaglandin synthesis.