Central role for fast nociceptors in mechanical nocifensive behavior and sensitization

Nociceptors, primary afferent nerve fibers that signal noxious stimuli, are broadly divided into slowly conducting unmyelinated C fibers and fast-conducting myelinated A fibers. Whereas C-nociceptors have been extensively studied, considerably less is known about the function of A-nociceptors. Here we demonstrate, combining genetic targeting of these fibers in mice with observations in human participants, a key involvement of A-nociceptors in mechanical nociceptive withdrawal reflexes and affective pain. In mice, optogenetic stimulation induced rapid and precise withdrawal reflexes as well as place aversion and facial expression changes consistent with pain affect, while inhibition strongly impaired mechanical nociceptive withdrawal reflexes. Prolonged A-nociceptor activation induced mechanical pain hypersensitivity and central sensitization. In a rare individual lacking thickly myelinated Aβ fibers, and in healthy participants during preferential Aβ-fiber nerve block, mechanical withdrawal reflexes were absent and mechanical pain perception reduced. Together, these findings identify fast-conducting mechano-nociceptors as essential drivers of nocifensive behaviors in mice and humans.