Two genetically distinct populations of fast-conducting Aδ high-threshold mechanoreceptors (Smr2Cre- and Bmpr1bCre-labeled) function as the primary mechanonociceptors in mice, densely innervating skin and internal organs with unique dual-laminar spinal projections that form strong monosynaptic connections onto anterolateral tract projection neurons and drive both ultrafast local spinal withdrawal reflexes and ascending pain pathways to mediate protective responses to damaging mechanical stimuli.

Nociceptors detect damaging stimuli and evoke pain in healthy animals. We conducted an optogenetic activation screen to identify genetically defined nociceptor populations that elicit place aversion and nocifensive behaviors in response to stimulation. Smr2Cre- and Bmpr1bCre-labeled Aδ high-threshold mechanoreceptors (HTMRs) emerged as two of the few nociceptor populations, and we focused on investigating their physiological, morphological, functional, and synaptic properties. These neurons densely innervate skin and other organs, are activated only by intense, potentially damaging stimuli, and are necessary for protective responses to sharp mechanical stimuli. Centrally, Aδ-HTMRs projections span multiple spinal segments and terminate across spinal cord laminae, forming strong, monosynaptic connections onto anterolateral tract projection neurons, including antenna cells of the deep dorsal horn. Aδ-HTMRs also engage a local spinal reflex circuit enabling a remarkably rapid limb withdrawal. Thus, Aδ-HTMRs are myelinated nociceptors with unique properties that can be exploited for development of new analgesics.