Involvement of primary sensory afferents, postganglionic sympathetic nerves and mast cells in the formalin-evoked peripheral release of adenosine

Injection of formalin into the rat hind paw produces a dose-dependent local peripheral release of adenosine. Low doses of formalin (0.5-2.5%) evoke release during the first 10 min following injection, while a high dose of formalin (5%) evokes release lasting for 60 min. The current study was designed to determine the possible origin of release produced by two doses of formalin (1.5% and 5%). Microdialysis probes were implanted into the subcutaneous tissue under the glabrous skin of the hind paw of anaesthetized rats, and adenosine was determined by high performance liquid chromatography. Pretreatment with capsaicin, a neurotoxin selective for unmyelinated small diameter primary afferent nerves, markedly reduced the adenosine released by 1.5% formalin and the early phase of release by 5% formalin. Acute injection of 1% capsaicin to the hind paw of untreated rats also induced adenosine release. Pretreatment with 6-hydroxydopamine, a neurotoxin selective for sympathetic postganglionic nerve terminals, had no effect on release evoked by 1.5% formalin, but significantly reduced adenosine release during the late phase of release induced by 5% formalin. Pretreatment with compound 48/80, which degranulates mast cells, had no effect on adenosine release evoked by either concentration of formalin. We conclude that the origin of the adenosine released peripherally by formalin depends on the formalin concentration. At the lower concentration (1.5%), release is predominately from unmyelinated sensory afferent nerve terminals, while at the higher concentration (5%), unmyelinated afferent nerve terminals are involved in the early phase, while sympathetic postganglionic nerve terminals are involved in the later phase. Mast cells do not contribute to release of adenosine evoked by either concentration of formalin.