Site-Specific Regulation of P2X7 Receptor Function in Microglia Gates Morphine Analgesic Tolerance
Autor: | Nicole E. Burma, Roger J. Thompson, Tuan Trang, Heather Leduc-Pessah, Nicholas L. Weilinger, Churmy Y. Fan |
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Rok vydání: | 2017 |
Předmět: |
Male
0301 basic medicine medicine.drug_class Analgesic Pharmacology Tyrosine-kinase inhibitor Rats Sprague-Dawley Mice 03 medical and health sciences 0302 clinical medicine medicine Animals Amino Acid Sequence Cells Cultured Injections Spinal Research Articles Pain Measurement Binding Sites Dose-Response Relationship Drug Morphine Microglia business.industry General Neuroscience Chronic pain Long-term potentiation Drug Tolerance medicine.disease Rats Analgesics Opioid 030104 developmental biology Nociception medicine.anatomical_structure Animals Newborn Opioid Receptors Purinergic P2X7 business Injections Intraperitoneal 030217 neurology & neurosurgery medicine.drug |
Zdroj: | The Journal of Neuroscience. 37:10154-10172 |
ISSN: | 1529-2401 0270-6474 |
Popis: | Tolerance to the analgesic effects of opioids is a major problem in chronic pain management. Microglia are implicated in opioid tolerance, but the core mechanisms regulating their response to opioids remain obscure. By selectively ablating microglia in the spinal cord using a saporin-conjugated antibody to Mac1, we demonstrate a causal role for microglia in the development, but not maintenance, of morphine tolerance in male rats. Increased P2X7 receptor (P2X7R) activity is a cardinal feature of microglial activation, and in this study we found that morphine potentiates P2X7R-mediated Ca2+responses in resident spinal microglia acutely isolated from morphine tolerant rats. The increased P2X7R function was blocked in cultured microglia by PP2, a Src family protein tyrosine kinase inhibitor. We identified Src family kinase activation mediated by μ-receptors as a key mechanistic step required for morphine potentiation of P2X7R function. Furthermore, we show by site-directed mutagenesis that tyrosine (Y382–384) within the P2X7R C-terminus is differentially modulated by repeated morphine treatment and has no bearing on normal P2X7R function. Intrathecal administration of a palmitoylated peptide corresponding to the Y382–384site suppressed morphine-induced microglial reactivity and preserved the antinociceptive effects of morphine in male rats. Thus, site-specific regulation of P2X7R function mediated by Y382–384is a novel cellular determinant of the microglial response to morphine that critically underlies the development of morphine analgesic tolerance.SIGNIFICANCE STATEMENTControlling pain is one of the most difficult challenges in medicine and its management is a requirement of a large diversity of illnesses. Although morphine and other opioids offer dramatic and impressive relief of pain, their impact is truncated by loss of efficacy (analgesic tolerance). Understanding why this occurs and how to prevent it are of critical importance in improving pain therapies. We uncovered a novel site (Y382–384) within the P2X7 receptor that can be targeted to blunt the development of morphine analgesic tolerance, without affecting normal P2X7 receptor function. Our findings provide a critical missing mechanistic piece, site-specific modulation by Y382–384, that unifies P2X7R function to the activation of spinal microglia and the development of morphine tolerance. |
Databáze: | OpenAIRE |
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