Neurochemical Studies of Reward from Pain Relief

Abstract

Chronic pain has been estimated to impact the economy of the United States by an annual cost of $635 billion per year and to affect approximately 100 million Americans (1). Pain is the primary reason patients seek medical attention yet physicians have few options for therapies and there remains a vast unmet medical need for effective and safe analgesics. Most of the drugs clinically available today either have limited efficacy or a variety of unwanted side effects. Discovery of novel therapeutics has been challenging with scientists struggling to find ways to better translate research from the bench-top to the bedside. One impediment in this process has been differences in preclinical and clinical assessment of pain. Preclinical models have historically relied heavily on evoked or reflexive endpoints in non-verbal animals while clinical measures of pain have the advantage of assessing changes in self-reported pain ratings. It is likely, and data from the studies reported in this dissertation show, that mechanisms that underlie threshold responses to evoked stimuli differ from those mediating affective (i.e., aversive) qualities of pain. A further confound is that many effective analgesics are narcotics that carry risk of addiction. Fear of addiction and possibly misuse for chronic treatment of pain may result in undertreatment in many patients. The most clinically relevant question in the management of pain is whether or not a treatment improves the patient's quality of life. Here, we demonstrate that the aversiveness of ongoing pain can be assessed using motivated behavior (conditioned place preference; CPP) and neurochemical output (in vivo NAc microdialysis). Additionally, we assessed the mechanistic effects of three clinically relevant analgesics. Our results show that: (1) pain relief is rewarding and activates reward circuitry that differs from circuits mediating addictive qualities of opiates, and (2) that drugs that mimic the consequences of engagement of descending inhibitory systems act by increasing spinal norepinephrine (NE) levels. These studies provide much needed information that helps build a platform from which more effective analgesics can be discovered and characterized in the preclinical setting and that may help in the introduction of new therapies for patients.