A population of primary afferent sensory neurons mediates pain relief through nocifensive coping behavior in mice

Proc Natl Acad Sci U S A. 2026 Jul 21;123(29):e2601766123. doi: 10.1073/pnas.2601766123. Epub 2026 Jul 15.

ABSTRACT

When exposed to noxious cutaneous stimuli, animals exhibit nocifensive behaviors, including rapid defensive reflexes that limit tissue damage and subsequent coping behaviors-most commonly licking of the affected area-that alleviate pain. Despite its ubiquity, the neural mechanism underlying pain relief through licking remains poorly understood. Here, we demonstrate that Npy2r-Cre⁺ primary sensory neurons in the dorsal root ganglion (DRG), a population of Aβ fibers that includes touch-sensitive, rapidly adapting low-threshold mechanoreceptors, are critical for this process. Mice lacking Npy2r-Cre⁺ neurons exhibited a significant prolongation of coping behavior duration, but not bout frequency, following intraplantar injection of capsaicin or formalin. Conversely, optogenetic activation of Npy2r-Cre⁺ neurons produced attenuating effects on irritant-induced pain. Electrophysiological analyses revealed that Npy2r-Cre⁺ neurons form functional synaptic connections with neurons in the substantia gelatinosa of the spinal dorsal horn (SDH) and that their activation suppressed C fiber-evoked excitation of neurons in lamina I of the SDH, a region implicated in nociceptive transmission to the brain. Together, these findings identify Npy2r-Cre⁺ DRG neurons as a key neural substrate for gating nociceptive transmission in the SDH and mediating pain relief through coping behaviors.

PMID:42455674 | DOI:10.1073/pnas.2601766123