['We examined the effects of systemically, spinally, and peripherally administered amitriptyline on formalin-induced Fos immunoreactivity in the lumbar spinal cord. Formalin (2.5%), injected subcutaneously into the rat hindpaw, increased Fos immunoreactivity in laminae I-II, III-IV, and V-VI of the dorsal L5 spinal cord. Amitriptyline, administered both systemically and spinally before formalin, increased flinching and concurrently decreased biting/licking behaviors, but neither route of administration produced any statistically significant change in Fos immunoreactivity. Amitriptyline coadministered with the formalin reduced both flinching and biting/licking behaviors, and significantly reduced Fos immunoreactivity, particularly in laminae I-II. These immunohistochemical changes reflect the net behavioral effects observed after the different routes of drug administration. The profile of amitriptyline action after peripheral administration may be of clinical importance because of the potential use of antidepressants as topical analgesics.'] Does peripheral amitriptyline suppress formalin-induced Fos expression in the rat spinal cord?