Assessments of Evoked and Spontaneous Pain Following Administration of Gabapentin and the Cannabinoid CB ₂ agonist LY2828360 in a Rat Model of Spared Nerve Injury

Cannabinoid CB ₂ agonists reduce stimulus-evoked behavioral hypersensitivities in preclinical pain models, but their ability to modulate spontaneous pain remains unexplored. Spontaneous pain has been assessed in rodents using the conditioned place preference (CPP) approach, given that the relief of pain is described as rewarding and results in negative reinforcement (i.e. removal of an aversive pain state). LY2828360 is a CB2 agonist that failed in a clinical trial for osteoarthritis pain. We compared impact of LY2828360 on evoked and spontaneous pain using a spared nerve injury (SNI) model in rats. First, we verified that an analgesic dose of gabapentin (100 mg/kg i.p.) produces CPP in rats with SNI, but not in sham-operated rats, consistent with a previous report (Griggs et al. 2015). We then used a within-subjects design to ascertain whether the CB ₂ agonist LY2828360 (10 mg/kg i.p., chronic) would suppress both evoked and spontaneous pain in rats with SNI. To assess evoked pain behavior, mechanical paw withdrawal thresholds were measured and revealed that LY2828360 reliably suppressed mechanical hypersensitivity in the paw ipsilateral , but not contralateral to SNI. Furthermore, efficacy was sustained across repeated injections without development of tolerance. To assess spontaneous pain behavior, we tested the ability of LY2828360 to prevent gabapentin-induced CPP in the SNI model, as failure to develop CPP to gabapentin following treatment with an analgesic has been considered evidence of suppression of spontaneous pain. The same rats that showed suppression of mechanically-evoked responses following chronic LY282860 treatment did not develop CPP to gabapentin. However, rats that were tested in parallel and treated chronically with vehicle showed robust mechanical hypersensitivity, but also did not develop CPP to gabapentin. These studies document that CB ₂ agonist-induced suppression of mechanically evoked pain is highly robust and reproducible, whereas CPP, used to assess spontaneous pain, is vulnerable to disruption and requires rigorous controls to rule out alternative explanations (e.g. failure to learn).