Chronic pain is a global problem that has reached epidemic proportions. An estimated 20% of adults suffer from pain, and another 10% are diagnosed with chronic pain each year (Goldberg and McGee, ). Despite the high prevalence of chronic pain (an estimated 1.5 billion people are afflicted worldwide), much remains to be understood about the underlying causes of this condition, and there is an urgent requirement for better pain therapies. The discovery of novel targets and the development of better analgesics rely on an assortment of preclinical animal models; however, there are major challenges to translating discoveries made in animal models to realized pain therapies in humans. This review discusses common animal models used to recapitulate clinical chronic pain conditions (such as neuropathic, inflammatory, and visceral pain) and the methods for assessing the sensory and affective components of pain in animals. We also discuss the advantages and limitations of modeling chronic pain in animals as well as highlighting strategies for improving the predictive validity of preclinical pain studies. © 2016 Wiley Periodicals, Inc.

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 Ca 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 (Y) 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 Y site suppressed morphine-induced microglial reactivity and preserved the antinociceptive effects of morphine in male rats. Thus, site-specific regulation of P2X7R function mediated by Y is a novel cellular determinant of the microglial response to morphine that critically underlies the development of morphine analgesic tolerance. Controlling 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 (Y) 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 Y, that unifies P2X7R function to the activation of spinal microglia and the development of morphine tolerance.

; CNS-central nervous system; CSF-cerebrospinal fluid; CCI-chronic constriction injury of the sciatic nerve; DH-SC-dorsal horn of the spinal cord; DTT-dithiothreitol; EDTA-ethylenediaminetetraacetic acid; EGTA-ethylene glycol-bis(β-aminoethyl ether)-tetraacetic acid; ELISA-enzymelinked immunosorbent assay; HEPES-4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid;