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.
Highlights
Following surgical procedures such as hernia repair, breast surgery, thoracotomy, cesarean section or coronary artery bypass surgery, patients develop acute postoperative pain that is characterized by mechanical hypersensitivity
Conclusions/Significance: Our results demonstrate that endocannabinoid signaling via cannabinoid receptors type 1 (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
To test our main hypothesis, we introduced a dual blockade of CB1 and CB2 receptors during the acute phase of paw incisioninduced mechanical allodynia
Summary
Following surgical procedures such as hernia repair, breast surgery, thoracotomy, cesarean section or coronary artery bypass surgery, patients develop acute postoperative pain that is characterized by mechanical hypersensitivity (pain due to ambulation, cough or manipulation of the surgical incision area). While this acute postoperative pain typically resolves, 10-50% of patients experience persistent postsurgical pain despite analgesic treatment, and 2-10% of patients develop severe chronic pain (rates depend on the procedure) [1]. We hypothesized that endocannabinoid signaling promotes the resolution of acute postoperative pain by modulating pro-inflammatory signaling in spinal cord glial cells
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