2018.05.11

Distinct functions of opioid-related peptides and gastrin-releasing peptide in regulating itch and pain in the spinal cord of primates.

Abstract

How neuropeptides in the primate spinal cord regulate itch and pain is largely unknown. Here we elucidate the sensory functions of spinal opioid-related peptides and gastrin-releasing peptide (GRP) in awake, behaving monkeys. Following intrathecal administration, β-endorphin (10-100 nmol) and GRP (1-10 nmol) dose-dependently elicit the same degree of robust itch scratching, which can be inhibited by mu-opioid peptide (MOP) receptor and GRP receptor (BB2) antagonists, respectively. Unlike β-endorphin, which produces itch and attenuates inflammatory pain, GRP only elicits itch without affecting pain. In contrast, enkephalins (100-1000 nmol) and nociceptin-orphanin FQ (3-30 nmol) only inhibit pain without eliciting itch. More intriguingly, dynorphin A(1-17) (10-100 nmol) dose-dependently attenuates both β-endorphin- and GRP-elicited robust scratching without affecting pain processing. The anti-itch effects of dynorphin A can be reversed by a kappa-opioid peptide (KOP) receptor antagonist nor-binaltorphimine. These nonhuman primate behavioral models with spinal delivery of ligands advance our understanding of distinct functions of neuropeptides for modulating itch and pain. In particular, we demonstrate causal links for itch-eliciting effects by β-endorphin-MOP receptor and GRP-BB2 receptor systems and itch-inhibiting effects by the dynorphin A-KOP receptor system. These studies will facilitate transforming discoveries of novel ligand-receptor systems into future therapies as antipruritics and/or analgesics in humans.

Distinct functions of opioid-related peptides and gastrin-releasing peptide in regulating itch and pain in the spinal cord of primates

Supplementary Information

Journal Club 18.05.04.

Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons
Radhika Palkar1,3, Serra Ongun1,2, Edward Catich1,3, Natalie Li1, Neil Borad1, Angela Sarkisian1 and David D. McKemy1,2,3

1Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California; 2Molecular and Computational Biology Graduate Program, Department of Biological Sciences, University of Southern California, Los Angeles, California; and 3Neuroscience Graduate Program, Department of Biological Sciences, University of Southern California, Los Angeles, California
Correspondence: David D. McKemy, Neurobiology Section, Department of Biological Sciences, University of Southern California, 3641 Watt Way, HNB 201, Los Angeles, CA 90089. E-mail: mckemy@dornsife.usc.edu
Abbreviations: Cqx, chloroquine; a-Me5-HT, a-methyl 5-HT
Received 16 August 2017; revised 8 December 2017; accepted 20 December 2017; accepted manuscript published online 27 December 2017; corrected proof published online XXX

Cooling Relief of Acute and Chronic Itch Requires TRPM8 Channels and Neurons

Cooling or the application of mentholated liniments to the skin has been used to treat itch for centuries, yet remarkably little is known about how counter-stimuli such as these induce itch relief. Indeed, there is no clear consensus in the scientific literature as to whether or not cooling does in fact block the transduction of itch signals or if it is simply a placebo effect. This gap in our understanding led us to hypothesize that cooling is antipruritic and, like cooling analgesia, requires function of the cold-gated ion channel TRPM8, a receptor for menthol expressed on peripheral afferent nerve endings. Using a combination of pharmacologic, genetic, and mouse behavioral assays, we find that cooling inhibits both histaminergic and non-histaminergic itch pathways, and that inhibition of itch by cooling requires TRPM8 channels or intact and functional TRPM8-expressing afferent neurons. The cold mimetic menthol is also effective in ameliorating itch in a TRPM8-dependent manner. Moreover, we find that chronic itch can be ameliorated by cooling, demonstrating that this counter-stimulus activates a specific neural circuit that leads to broad itch relief and a potential cellular mechanism for treatment of chronic itch.
Journal of Investigative Dermatology (2018) -, -e-; doi:10.1016/j.jid.2017.12.025

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