Recent psychophysical and electrophysiological studies in humans suggest the existence of two peripheral pathways for itch, one that is responsive to histamine and a second pathway that can be activated by nonhistaminergic pruritogens (e.g., cowhage spicules). To explore the peripheral neuronal pathway for nonhistaminergic itch, behavioral responses and neuronal activity in unmyelinated afferent fibers were assessed in monkey after topical application of cowhage spicules or intradermal injection of histamine and capsaicin. Cowhage and histamine, but not capsaicin, evoked scratching behavior indicating the presence of itch. In single-fiber recordings, cowhage, histamine and/or capsaicin were applied to the cutaneous receptive field of 43 mechano-heat-sensitive C-fiber (CMH) nociceptors. The majority of CMHs exhibited a prolonged response to cowhage (39 of 43) or histamine (29 of 38), but not to capsaicin (3 of 34). Seven CMHs were activated by cowhage but not histamine. The average response to cowhage was more than twice the response to histamine, and responses were not correlated. The response of the CMHs to a stepped heat stimulus (49°C, 3 s) was either quickly adapting (QC) or slowly adapting (SC). In contrast, the cowhage response was characterized by bursts of two or more action potentials (at ∼1 Hz). The total cowhage response of the QC fibers (97 action potentials/5 min) was twice that of the SC fibers (49 action potentials/5 min). A subset of QC fibers exhibited high-frequency intraburst discharges (∼30 Hz). These results suggest multiple mechanisms by which CMHs may encode itch to cowhage as well as pain to mechanical and heat stimuli.
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