Manalo, A. P. | bioRxiv Science

bioRxiv2026

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

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 BriefKooij 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. HighlightsO_LISpinal KOR signaling suppresses behavioral responses in rodent acute pain models C_LIO_LIChemogenetic activation of Oprk1Crespinal neurons elicits nocifensive behaviors C_LIO_LIKOR is expressed on excitatory superficial dorsal horn neurons that contain the pain-promoting neuropeptide Tac1 (Substance P) in mouse C_LIO_LIKOR-expressing spinal neurons similarly reside in the superficial dorsal horn and coexpress TAC1 in human C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=147 HEIGHT=200 SRC="FIGDIR/small/735618v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1a6e5a2org.highwire.dtl.DTLVardef@2e28f9org.highwire.dtl.DTLVardef@83f593org.highwire.dtl.DTLVardef@16fc0a1_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2023

Identification of a convergent spinal neuron population that encodes itch

Itch is a protective sensation that drives scratching. Although specific cell types have been proposed to underlie itch, the neural circuit basis for itch remains unclear. Here, we used two-photon Ca2+ imaging of the dorsal horn to visualize the neuronal populations that are activated by itch-inducing agents. We identify a convergent population of spinal neurons that is defined by the expression of GRPR. Moreover, we discover that itch is conveyed to the brain via GRPR-expressing spinal output neurons that target the lateral parabrachial nucleus. Further, we show that nalfurafine, a clinically effective kappa opioid receptor agonist, relieves itch by inhibiting GRPR spinoparabrachial neurons. Finally, we demonstrate that a subset of GRPR spinal neurons show persistent, cell-intrinsic Ca2+ oscillations. These experiments provide the first population-level view of the spinal neurons that respond to pruritic stimuli, pinpoint the output neurons that convey itch to the brain, and identify the cellular target of kappa opioid receptor agonists for the inhibition of itch. In briefThrough population imaging, Sheahan et al. identify a network of neurons in the dorsal horn that is activated by pruritogens and find that kappa opioid receptor signaling inhibits itch through the selective inhibition of GRPR spinoparabrachial neurons. HighlightsO_LIItch-inducing agents drive activity in a common population of GRPR-expressing spinal interneurons C_LIO_LIGRPR spinal projection neurons transmit itch from the spinal cord to the brain C_LIO_LIKappa opioids reduce itch through the inhibition of GRPR spinoparabrachial neurons C_LIO_LIGRPR activation elicits persistent, intrinsic Ca2+ oscillations C_LI

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