Sex Dependent Reduction In Mechanical Allodynia In The Sural-Sparing Nerve Injury Model In Mice Lacking Merkel Cells

Innocuous touch sensation is mediated by cutaneous low-threshold mechanoreceptors (LTMRs). A beta slowly adapting type 1 (SA1) neurons constitute one LTMR subtype that forms synapse-like complexes with associated Merkel cells in the basal skin epidermis. Under healthy conditions, these complexes transduce indentation and pressure stimuli into A beta SA1 LTMR action potentials that are transmitted to the central nervous system, thereby contributing to tactile sensation. However, it remains unknown whether this complex plays a role in the mechanical hypersensitivity caused by peripheral nerve injury. In this study, we characterized the distribution of Merkel cells and associated afferent neurons across four diverse domains of mouse hind paw skin, including a recently described patch oplantar hairy skin. We also showed that in the spared nerve injury (SNI) model of neuropathic pain, Merkel cells are lost from the denervated tibial nerve territory, but are relatively preserved in nearby hairy skin innervated by the spared sural nerve. Utilizing a genetic Merkel cell knockout mouse model, we subsequently examined the importance of intact Merkel cell-A beta complexes to SNI-associated mechanical hypersensitivity in skin innervated by the spared neurons. We found that in the absence of Merkel cells, mechanical allodynia was partially reduced in male mice, but not female mice, under sural-sparing SNI conditions. Our results suggest that Merkel cell-A beta afferent complexes partially contribute to mechanical allodynia produced by peripheral nerve injury, and that they do so in a sex dependent manner.Significance StatementMerkel discs or Merkel cell-A beta afferent complexes are mechanosensory end organs in mammalian skin. Yet, it remains unknown whether Merkel cells or their associated sensory neurons play a role in the mechanical hypersensitivity caused by peripheral nerve injury. We found that male mice genetically lacking Merkel cell-A beta afferent complexes exhibited a reduction in mechanical allodynia after nerve injury. Interestingly, this behavioral phenotype was not observed in mutant female mice. Our study will facilitate understanding of mechanisms underlying neuropathic pain.