CENTRAL SENSORIMOTOR CHANGES DUE TO PERIPHERAL NERVE INJURY: ROLE OF DOPAMINERGICS AND OPIOIDS

Abstract

Chronic neuropathic pain (CNP) is a disease typically resulting from injury to the central or peripheral nervous system. CNP has a prevalence of 12-15% in the population, but current treatments are not highly efficacious in achieving long term analgesia. Chronic use of opioids is a typical but dangerous regimen that usually requires high doses to achieve analgesia, putting patients at elevated risk for opioid overdose and negative side effects. We have previously shown that adjuvant administration of a dopamine (DA) D3 receptor agonist, pramipexole (PPX), with morphine achieved analgesia in in a centrally induced model of CNP. Here we used a more clinically relevant disease of peripherally induced CNP (sciatic nerve ligation, SNL) to test if this treatment would be more effective than morphine. To test these hypotheses, male mice (C57BL/6) underwent a unilateral SNL, and thermal pain withdrawal reflex latencies (TPWRLs) were measured on injured and uninjured sides under control and drug treatment conditions. We found that neither morphine nor PPX alone restored TPWRLs, which are decreased after SNL, but that administering both drugs as an adjuvant therapy (morphine + PPX) under acute conditions led to a synergistic effect that fully restored TPWRLs to pre-injury baseline levels. With this approach, a full analgesic effect was observed even after reducing the morphine dose by 50%. Next, we tested if continuous daily treatment with the adjuvant (morphine + PPX) at its lower dose could maintain analgesia over time. We found that chronic treatment with the combination mimicked the acute effects, in that it restored and maintained TPWRLs on the SNL side at levels similar to those of the contralateral un-injured sides, and effect was maintained over time. Animals showed no sign of recovery from injury, or tolerance to treatment. In addition, we tested with extracellular electrophysiology for the effects of SNL and subsequent drug treatments on compound action potentials (CAPs) in injured and un-injured sciatic nerves. To test this, we conducted a series of analyses and found that CAPs of injured nerves were consistently lower than those of their contralateral controls. We found that CAPs were lost after SNL and that they did not recover after prolonged treatment with either morphine or PPX, but that they showed a trend towards a recovery after long-term treatment with the drug combination. In conclusion, our data indicate adjuvant treatment of a D3 agonist with morphine can achieve and maintain analgesia over time, and this effect may be mediated in part by changes in the injured sciatic nerves themselves. Combining these data with our previous studies suggests that this adjuvant may serve as a new pharmacological treatment for CNP regardless of its origin. Ultimately, these findings may lead to the development of a novel effective method of pain relief that reduces negative side effects of using high dose opioids, and they may contribute to a potential reduction of the opioid epidemic.