Physiological, morphological, synaptic, and behavioral analyses of genetically defined myelinated nociceptors

Abstract

Pain can be both devastating to individuals and costly to the healthcare system. Yet, our understanding of pain biology and the primary sensory neurons that drive pain, nociceptors, is incomplete. We recently generated two mouse lines, Smr2Cre and Bmpr1bCre, that label A fiber high-threshold mechanoreceptors (A-HTMRs) in hairy skin and hypothesized that the labeled neurons are myelinated nociceptors. Here, we report on physiological, morphological, functional, and synaptic analyses of genetically defined myelinated nociceptors in non-hairy, or glabrous, skin to understand their unique contribution to the experience of pain. The A-HTMRs are found to be among the few somatosensory neuron types capable of evoking place aversion and nocifensive behaviors in response to minimal stimulation. Consistent with the original definition of a nociceptor, these neurons are activated only by very intense stimuli. Both A-HTMR populations are necessary for protective responses to sharp mechanical stimuli. These protective neurons densely innervate the skin and a variety of other organs, including joints and cranial meninges. Centrally, A-HTMRs form unique projections that span multiple spinal segments and terminate in the superficial and deep laminae of the spinal cord dorsal horn, where they form monosynaptic connections on projection neurons of the anterolateral tract. A-HTMRs also engage a local spinal reflex circuit that enables quick paw withdrawal in response to damaging stimuli. Thus, A-HTMRs are bona fide myelinated nociceptors with unique physiological, morphological, and synaptic properties. Future work on characterizing and manipulating these neurons may yield important insights for the development of analgesics.