Evidence for a Role of Endocannabinoids, Astrocytes and p38 Phosphorylation in the Resolution of Postoperative Pain

Abstract

BackgroundAn alarming portion of patients develop persistent or chronic pain following surgical procedures, but the mechanisms underlying the transition from acute to chronic pain states are not fully understood. In general, endocannabinoids (ECBs) inhibit nociceptive processing by stimulating cannabinoid receptors type 1 (CB1) and type 2 (CB2). We have previously shown that intrathecal administration of a CB2 receptor agonist reverses both surgical incision-induced behavioral hypersensitivity and associated over-expression of spinal glial markers. We therefore hypothesized that endocannabinoid signaling promotes the resolution of acute postoperative pain by modulating pro-inflammatory signaling in spinal cord glial cells.Methodology/Principal Findings To test this hypothesis, rats receiving paw incision surgery were used as a model of acute postoperative pain that spontaneously resolves. We first characterized the concentration of ECBs and localization of CB1 and CB2 receptors in the spinal cord following paw incision. We then administered concomitant CB1 and CB2 receptor antagonists/inverse agonists (AM281 and AM630, 1 mg.kg−1 each, i.p.) during the acute phase of paw incision-induced mechanical allodynia and evaluated the expression of glial cell markers and phosphorylated p38 (a MAPK associated with inflammation) in the lumbar dorsal horn. Dual blockade of CB1 and CB2 receptor signaling prevented the resolution of postoperative allodynia and resulted in persistent over-expression of spinal Glial Fibrillary Acidic Protein (GFAP, an astrocytic marker) and phospho-p38 in astrocytes. We provide evidence for the functional significance of these astrocytic changes by demonstrating that intrathecal administration of propentofylline (50 µg, i.t.) attenuated both persistent behavioral hypersensitivity and over-expression of GFAP and phospho-p38 in antagonist-treated animals.Conclusions/Significance Our results demonstrate that endocannabinoid signaling via CB1 and CB2 receptors is necessary for the resolution of paw incision-induced behavioral hypersensitivity and for the limitation of pro-inflammatory signaling in astrocytes following surgical insult. Our findings suggest that therapeutic strategies designed to enhance endocannabinoid signaling may prevent patients from developing persistent or chronic pain states following surgery.

A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors

“…This model, in which a surgical incision in the animal’s hind paw causes thermal and tactile hypersensitivity, displays similarities to the human postoperative pain syndrome and relies on CaV2.2 for pain signal transmission. 17 Mechanistically, p38, a Cdk5 substrate, 77 is hyperphosphorylated in DRG during postsurgical pain, 2 reflecting increased Cdk5 activity. We reported that Cdk5-mediated CRMP2 phosphorylation increases its binding to CaV2.2, which augments calcium influx 11 ; thus, the increased interaction between CRMP2 and CaV2.2 may underlie the mechanism of antinociception in this particular model.…”

Endocannabinoid system and pain: an introduction

“…Conversely, overexpression of CB 2 receptors protected against nerve injury-induced thermal and mechanical allodynia and prevented glial activation in the spinal cord. Numerous other studies have also implicated EC signalling in glial cell activation (64,103,104) .…”

Endogenous Analgesia, Dependence, and Latent Pain Sensitization

“…For example, conditional knockdown of neuropeptide tyrosine (NPY) before the initiation of inflammation extended the time course of mechanical and heat hyperalgesia (Solway et al, 2011). Similarly, dual blockade of cannabinoid CB1 and CB2 receptor signaling prevents the resolution of postoperative allodynia (Alkaitis et al, 2010). These studies indicate that endogenous NPY and endocannabinoids hasten the resolution of inflammatory and neuropathic pain.…”

“…However, numerous receptor systems besides MOR likely maintain LS in remission, LS is masked not only by opioid receptor activity, but also by endocannabinoids (Alkaitis et al, 2010, Ji et al, 2011), alpha-2 adrenergic receptors (De Felice et al, 2011), and neuropeptide Y (NPY) receptor activity (Solway et al, 2011). For example, our lab recently used conditional NPY knockout mice and NPY Y1 and Y2 receptor antagonists to demonstrate that the endogenous NPY system in the DH is involved in repressing the LS induced by inflammation or nerve damage (Solway et al, 2011).…”