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Background context There is increasing evidence for a role of the cannabinoid (CB) system in the development of neuropathic pain (NP) after spinal cord injury (SCI). The nonspecific CB 1 and CB 2 receptor agonists, WIN 55, 212-2 (WIN), have previously been shown to alleviate both mechanical and thermal hyperalgesia (TH) after peripheral nerve injury. Purpose The present study was designed to identify the CB receptors involved in the antihyperalgesic effect of WIN by using selective antagonists for CB 1 and CB 2 receptors. Study design This is an in vivo and behavioral study using a moderate T9 contusion SCI. After injury, TH of the hind paws was measured on postinjury days 21 through 42. Methods Sprague-Dawley rats underwent a contusion SCI using the Multicenter Animal Spinal Cord Injury Study (MASCIS) weight-drop impactor, which induced a moderate T9 SCI. Only animals showing consistent plantar stepping and consistent forelimb and hind limb coordination (Basso, Beattie, and Bresnahan score=15) were tested for TH. Animals exhibiting decreased withdrawal latency time, indicating TH, on or before Day 42, were selected for pharmacological intervention. Animals not exhibiting TH did not receive pharmacological intervention and were sacrificed. Rats underwent hind paw testing before any drug administration (after injury), 45 minutes after selective CB antagonist (AM 251 or AM 630) administration (postantagonist) and again 45 minutes after WIN administration (post-WIN). There were a total of seven treatment groups: saline vehicle control; Dimethyl sulfoxide (DMSO) vehicle control; low-dose WIN (0.2 mg/kg); and high-dose WIN (2.0 mg/kg); AM 251 (3 mg/kg) and AM 630 (1 mg/kg) were given subcutaneously in a total volume of 0.5 mL. Followed by intraperitoneal injection of WIN after each antagonist, sham-operated rats repeated pharmacological intervention used with treatment Groups 5 and 6. Results Thermal hyperalgesia was significantly ameliorated in a dose-dependent manner with systemically administered WIN. Cannabinoid receptor Type 1 antagonist AM 251 pretreatment did not affect the antihyperalgesic effect of WIN. By contrast, pretreatment with the CB 2 receptor antagonist AM 630 significantly attenuated the effect of WIN. Conclusion Taken together, these results suggest a role of the CB 2 receptor in modulating SCI-induced TH. Selective activation of the CB 2 receptor could potentially lead to analgesic effects on NP while avoiding psychotropic side effects in patients with SCI.