Fanien, L. G. | 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

neuroscience↗

bioRxiv2020

The neurokinin-1 receptor is expressed with gastrin-releasing peptide receptor in spinal interneurons and modulates itch

The neurokinin-1 receptor (NK1R, encoded by Tacr1) is expressed in spinal dorsal horn neurons and has been suggested to mediate itch. However, previous studies relied heavily on neurotoxic ablation of NK1R spinal neurons, which limited further dissection of their function in spinal itch circuitry. Thus, we leveraged a newly developed Tacr1CreER mouse line to characterize the role of NK1R spinal neurons in itch. We show that pharmacological activation of spinal NK1R and chemogenetic activation of Tacr1CreER spinal neurons increases itch behavior, whereas pharmacological inhibition of spinal NK1R suppresses itch behavior. We use fluorescence in situ hybridization to characterize the endogenous expression of Tacr1 throughout the superficial and deeper dorsal horn, as well as the lateral spinal nucleus. Retrograde labeling studies from the parabrachial nucleus show that less than 20% of superficial Tacr1CreER dorsal horn neurons are spinal projection neurons, and thus the majority of Tacr1CreER are local interneurons. We then use a combination of in situ hybridization and ex vivo two-photon Ca2+ imaging of the spinal cord to establish that NK1R and the gastrin-releasing peptide receptor (GRPR) are coexpressed within a subpopulation of excitatory superficial dorsal horn neurons. These findings are the first to describe a role for NK1R interneurons in itch and extend our understanding of the complexities of spinal itch circuitry.

neuroscience↗