Kappa opioid receptors in excitatory spinal neurons gate acute pain: evidence from mouse and human

bioRxiv [Preprint]. 2026 Jul 6:2026.07.01.735618. doi: 10.64898/2026.07.01.735618.

ABSTRACT

The kappa opioid receptor (KOR) has emerged as a promising, nonaddictive analgesic target, yet the neural mechanisms underlying KOR inhibition of pain are not entirely understood. Here, we provide converging evidence that KOR expressed on spinal neurons inhibits acute pain. We demonstrate that pharmacological inhibition of KOR-expressing neurons in the spinal cord blocks nocifensive behaviors. Conversely, chemogenetic activation of KOR-expressing spinal neurons elicits nocifensive behaviors. We then perform a series of molecular characterizations and show that excitatory KOR spinal neurons are recruited by noxious stimuli and coexpress pain-promoting neuropeptides such as Tac1 in both mouse and human. Together, these data suggest that kappa opioids inhibit pain by reducing the release of pain-promoting neuropeptides from a translationally relevant population of spinal neurons.

IN BRIEF: Kooij et al. find KOR signaling within the spinal cord suppresses pain transmission. Molecular characterization of KOR-expressing spinal neurons reveals this may occur through the inhibition of excitatory spinal neurons, which also express pain-promoting neuropeptides.

HIGHLIGHTS: Spinal KOR signaling suppresses behavioral responses in rodent acute pain models Chemogenetic activation of Oprk1 ^Cre spinal neurons elicits nocifensive behaviors KOR is expressed on excitatory superficial dorsal horn neurons that contain the pain-promoting neuropeptide Tac1 (Substance P) in mouseKOR-expressing spinal neurons similarly reside in the superficial dorsal horn and coexpress TAC1 in human.

PMID:42465398 | PMC:PMC13370457 | DOI:10.64898/2026.07.01.735618