Endocannabinoid activation of CB 1 receptors contributes to long‐lasting reversal of neuropathic pain by repetitive spinal cord stimulation

Background Spinal cord stimulation ( SCS ) has been shown to be effective in the management of certain neuropathic pain conditions, however, the underlying mechanisms are incompletely understood. In this study, we investigated repetitive SCS in a rodent neuropathic pain model, revealing long‐lasting and incremental attenuation of hyperalgesia and a mechanism of action involving endocannabinoids. Method Animals were implanted with monopolar electrodes at the time of partial sciatic nerve injury. Dorsal columns at spinal segments T12/13 were stimulated 3 days later (early SCS ), and again at day 7 (late SCS ) using low‐frequency parameters. Hypersensitivity to cutaneous mechanical stimuli was assessed using von Frey filaments. Pharmacological agents, selected to identify endocannabinoid and opioid involvement, were administered intraperitoneally, 10 min before SCS . Results Early SCS caused partial reversal of mechanical hypersensitivity with corresponding changes in the biomarker of central sensitization, [phospho‐Tyr 1472 ]‐GluN2B. The partial reversal of hyperalgesia by early SCS was amplified by co‐administration of LY 2183240, an inhibitor of endocannabinoid reuptake/breakdown. This amplification was inhibited by a CB 1 R antagonist, AM 251, but not by a CB 2 R antagonist, AM 630. Early SCS ‐induced reversal of hyperalgesia was attenuated by naloxone, indicating a role for opioids. Late SCS resulted in an incremental level of reversal of hyperalgesia, which was inhibited by AM 251, but not by CB 2 or opioid receptor antagonists. Conclusion The endocannabinoid system, and in particular the CB 1 R, plays a pivotal role in the long‐lasting and incremental reversal of hyperalgesia induced by repetitive SCS in a neuropathic pain model. Significance Alternative parameters for repetitive spinal cord stimulation ( SCS ) at 25/10 Hz elicit particularly long‐lasting and incremental reversal of hyperalgesia in a neuropathic pain model through a mechanism involving endocannabinoids.