Fast-conducting mechanonociceptors uniquely engage reflexive and affective pain circuitry to drive protective responses

Lezgiyeva, K.; Liu, J.; Nguyen, K.; DeLisle, M. M.; Ko, F. C.; Fullam, S.; Obeidat, A. M.; Turecek, J.; Alkislar, I.; Lehnert, B. P.; Martinez-Garcia, R. I.; Sivakumar, R.; Choi, J.; Mazor, O.; Garibyan, L.; Sharma, N.; Emanuel, A. J.; Malfait, A.-M.; Miller, R. E.; Ginty, D. D.

doi:10.1101/2025.11.11.687663

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bioRxiv · 10.1101/2025.11.11.687663

Fast-conducting mechanonociceptors uniquely engage reflexive and affective pain circuitry to drive protective responses

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Abstract

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 A{delta} 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, A{delta}-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. A{delta}-HTMRs also engage a local spinal reflex circuit enabling a remarkably rapid limb withdrawal. Thus, A{delta}-HTMRs are myelinated nociceptors with unique properties that can be exploited for development of new analgesics.

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Lezgiyeva, K., Liu, J., Nguyen, K., DeLisle, M. M., Ko, F. C., Fullam, S., Obeidat, A. M., Turecek, J., Alkislar, I., Lehnert, B. P., Martinez-Garcia, R. I., Sivakumar, R., Choi, J., Mazor, O., Garibyan, L., Sharma, N., Emanuel, A. J., Malfait, A.-M., Miller, R. E., Ginty, D. D.. 2025-11-12. Fast-conducting mechanonociceptors uniquely engage reflexive and affective pain circuitry to drive protective responses. https://doi.org/10.1101/2025.11.11.687663

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