β-Arrestin-2-Biased Agonism of Delta Opioid Receptors Sensitizes Transient Receptor Potential Vanilloid Type 1 (TRPV1) in Primary Sensory Neurons

• Published in: Molecular pain Vol. 10; no. 1; p. 50
• Main Authors: Rowan, Matthew P, Szteyn, Kalina, Doyle, Allison P, Gomez, Ruben, Henry, Michael A, Jeske, Nathaniel A
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.08.2014; Sage Publications Ltd; BioMed Central Ltd; BioMed Central
• Subjects: Addictions; Agonists; Animals; Arrestin; Arrestins - metabolism; Benzamides - pharmacology; beta-Arrestin 2; beta-Arrestins; Capsaicin - toxicity; Capsaicin receptors; Cells, Cultured; Chronic pain; Constipation; Disease Models, Animal; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Lectins - metabolism; Male; Mice; Mice, Inbred C57BL; Narcotics; Opioid receptors (type delta); Opioid receptors (type mu); Pain perception; Pain Threshold - drug effects; Piperazines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu - agonists; Sensory neurons; Sensory Receptor Cells - drug effects; Sensory System Agents - toxicity; Side effects; Species Specificity; Time Factors; Transient receptor potential proteins; Trigeminal Ganglion; TRPV Cation Channels - metabolism; Allodynia; Opioid; Chronic pain; Hyperalgesia
• ISSN: 1744-8069; 1744-8069
• DOI: 10.1186/1744-8069-10-50

Despite advances in understanding the signaling mechanisms involved in the development and maintenance of chronic pain, the pharmacologic treatment of chronic pain has seen little advancement. Agonists at the mu opioid receptor (MOPr) continue to be vital in the treatment of many forms of chronic pain, but side-effects limit their clinical utility and range from relatively mild, such as constipation, to major, such as addiction and dependence. Additionally, chronic activation of MOPr results in pain hypersensitivity known as opioid-induced hyperalgesia (OIH), and we have shown recently that recruitment of β-arrestin2 to MOPr, away from transient potential vanilloid eceptor type 1 (TRPV1) in primary sensory neurons contributes to this phenomenon. The delta opioid receptor (DOPr) has become a promising target for the treatment of chronic pain, but little is known about the effects of chronic activation of DOPr on nociceptor sensitivity and OIH. Here we report that chronic activation of DOPr by the DOPr-selective agonist, SNC80, results in the sensitization of TRPVI and behavioral signs of OIH via β-arrestin2 recruitment to DOPr and away from TRPV1. Conversely, chronic treatment with ARM390, a DOPr-selective agonist that does not recruit β-arrestin2, neither sensitized TRPV1 nor produced OIH. Interestingly, the effect of SNC80 to sensitize TRPV1 is species-dependent, as rats developed OIH but mice did not. Taken together, the reported data identify a novel side-effect of chronic administration of β-arrestin2-biased DOPr agonists and highlight the importance of potential species-specific effects of DOPr agonists.