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