Assessments of evoked and spontaneous pain following administration of gabapentin and the cannabinoid CB2 agonist LY2828360 in a rat model of spared nerve injury

Cannabinoid CB2 agonists reduce stimulus-evoked behavioral hypersensitivities in preclinical pain models, but their ability to modulate spontaneous pain remains largely 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 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 in a spared nerve injury (SNI) model using a within-subjects design in rats. First, we used an unbiased CPP approach to verify that an analgesic dose of gabapentin (100 mg/kg, i.p.) produces CPP in rats with SNI, but not in sham-operated rats. We then used a within-subjects design to ascertain whether LY2828360 (10 mg/kg i.p., chronic) would suppress both evoked and spontaneous pain in rats with SNI. To assess evoked pain behavior, paw withdrawal thresholds were measured in the same rats used for CPP. 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/affective pain behavior, we tested the ability of chronic dosing with LY2828360, in comparison to vehicle, 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 CB2 agonist-induced suppression of mechanically-evoked pain is highly robust and reproducible in the SNI model, 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).