Naked mole-rats lack substance P and CGRP in cutaneous nerve fibers, and dorsal root ganglia cells (SFN Abs 2000, 26 p 126). These peptides are thought to be neurotransmitters released from capsaicin-sensitive C polymodal nociceptors. The present experiments were designed to investigate the effects of natural SP and CGRP absence on the nociception, and to determine whether C-fiber or A-delta nociceptor activity is differentially affected by the absence of these peptides. We used foot withdrawal to noxious heating, and the formalin test. In skin heating, high rates of heating predominantly activate A-delta fibers. Low rates of heating predominantly activate C fibers, which can be sensitized by topical application of a low dose of capsaicin, shortening withdrawal latency. In naked mole-rat skin, capsaicin application (2nM or 10nM) caused no changes in presumptive C-fiber mediated withdrawal compared to control rats and mice. In the formalin test (1% 50ml), naked mole-rats, compared to mice, showed significan...