Abstract
Peripherally-restricted kappa opioid receptor (KOR) agonists are emerging as a novel treatment for pain and itch conditions and have shown efficacy in several recent clinical trials. One primary site of action is thought to be at KORs on primary afferent nerves that innervate the body. Yet, the subtypes of primary afferent somatosensory neurons that express the kappa opioid receptor remain undefined. Using a newly developed KOR-cre knockin allele, viral tracing, and single-cell RT-PCR we discovered that that KOR is expressed in a specific subset of peptidergic afferents. This subset targeted multiple tissue types and expressed higher levels of transcripts known to be involved in neurogenic inflammation. Consistent with this, peripherally-restricted KOR agonists inhibited behavioral responses to chemical pain and itch stimuli, but not acute heat stimuli, and also decreased mechanical hypersensitivity following an incision injury. Unexpectedly, we also found that KOR is expressed in subsets of primary afferents that form lanceolate or circumferential endings around hair follicles, suggesting an unappreciated role for KOR signaling in the modulation of low-threshold mechanosensation. At a functional level, genetically-labeled afferents showed inhibition of voltage-gated calcium current in response to kappa agonists, and optogenetic experiments revealed that dynorphin inhibited evoked-EPSCs from the central terminals of KOR-expressing afferents. These experiments provide key insight for the rationale use of peripherally-restricted KOR agonists for the modulation of inflammatory pain, itch, and potentially mechanical allodynia.
Highlights
As we are interested in how the nervous system processes somatosensory information and in developing better treatments for pain and itch conditions, the first cell type(s) expressing KOR we wanted to characterize were primary sensory afferents in the DRG
These results show that using viral techniques to infect primary afferent neurons in adult KOR-cre mice is sufficient to cause recombination in primary afferents that are highly likely to express KOR, as the majority express Oprk[1] mRNA, and that this approach is specific as cells that do not show recombination with the KOR-cre allele do not express Oprk[1] mRNA
We have provided evidence that supports the use of KOR-cre allele to identify, target, and characterize primary afferents that express KOR in adult mice
Summary
As we are interested in how the nervous system processes somatosensory information and in developing better treatments for pain and itch conditions, the first cell type(s) expressing KOR we wanted to characterize were primary sensory afferents in the DRG. Several recent papers have described analyses of transcripts on a single cell level, as unique transcript expression profiles may lead to novel definitions of cell types and may provide new insights into functional properties of sensory afferents (Usoskin et al, 2015; Li et al, 2016; Chiu et al, 2014). A reliable tool to identify KOR-expressing neurons is much needed to progress our understanding of the characteristics of these afferents, the role of KOR signaling in somatosensation, and how best to target this receptor for therapeutic use. Understanding the types of primary afferents that express KOR provides an opportunity to investigate the effect of KOR signaling on somatosensory transmission with more granularity. Several studies measuring neuropeptide release report no effect of KOR agonists on either SP (Zachariou (Zachariou & Goldstein, 1996); (Hirota et al, 1985) or CGRP (Collin et al, 1993); (Ballet et al, 1998) levels in the dorsal horn following primary afferent stimulation
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