Analgesic treatment with pregabalin does not prevent persistent pain after peripheral nerve injury in the rat

Abstract

Reducing the risk of chronic postoperative pain through preventive analgesia is an attractive therapeutic concept. Because peripheral nerve lesions are a major cause of chronic pain after surgery, we tested in rats whether analgesic treatment with pregabalin (PGB) has the capacity to mitigate the development of persistent neuropathic pain-like behavior. Starting on the day of spared nerve injury or 1week later, we treated rats with a continuous intrathecal infusion of PGB (300 or 900μg/24hours) or vehicle for up to 28days. Rats receiving early PGB treatment had almost normal withdrawal thresholds for punctate mechanical stimuli and were clearly less sensitive to pinprick or cold stimulation. The responses to punctate mechanical and cold stimulation were still reduced for a brief period after the infusion was terminated, but the difference from vehicle-treated rats was minor. Essentially, the analgesic effect of PGB was limited to the duration of the infusion, whether analgesia started at the time of surgery or with a delay of 1week, independently of the length of the treatment. PGB did not suppress the activation of spinal microglia, indicating that analgesia alone does not eliminate certain pain mechanisms even if they depend, at least partially, on nociceptive input. Unexpectedly, intrathecal infusion of PGB did not inhibit the nerve injury-induced accumulation of its binding target, the voltage-gated calcium channel subunit α2δ1, at primary afferent terminals in the spinal cord. Interference with the synaptic trafficking of α2δ1 is not required to achieve analgesia with PGB.

Keywords: Neuropathic pain; Postoperative pain; Pregabalin; Preventive analgesia.