Abstract
Chronic pain is a main symptom of osteoarthritis (OA). Moreover, a high percentage of OA patients suffer from mental health problems. The endocannabinoid (EC) system has attracted attention as an emerging drug target for pain treatment together with its activity on the mesolimbic reward system. Understanding the circuits that govern the reward of pain relief is crucial for the search for effective analgesics. Therefore, we investigated the role of the EC system on dopamine (DA) and noradrenaline (NA) in an animal model of OA-related chronic pain. OA rats exhibited significant decreases in DA metabolism in the nucleus accumbens (NAc), striatum (STR) and hippocampus (HC). NA metabolism was also significantly decreased by chronic pain in OA rats; however, this disruption was limited to the frontal cortex (FCx) and HC. URB597 (an inhibitor of EC metabolism) treatment completely reversed the decreased DA metabolism, especially in the brain reward system and the HC. Furthermore, administration of URB597 normalized the impairment of NA activity in the HC but potentiated the decreased NA levels in the FCx. Our results demonstrated that chronic pain in OA rats was reflected by the inhibition of mesolimbic and mesocortical dopaminergic transmission, and may indicate the pro-pain role of NA in the FCx. The data provide understanding about changes in neurotransmission in chronic pain states and may explain the clinical improvement in perceived life quality following cannabinoid treatment. Additional mechanistic studies in preclinical models examining the intersection between chronic pain and reward circuits may offer new approaches for improving pain therapy.
Highlights
According to the International Association for the Study of Pain (IASP), pain is defined as a complicated phenomenon compromising an unpleasant sensory and emotional experience associated with actual or potential tissue damage
Our results demonstrated that chronic pain in OA rats was reflected by the inhibition of mesolimbic and mesocortical dopaminergic transmission, and may indicate the pro-pain role of NA in the frontal cortex (FCx)
Rates of DA Metabolism One-way ANOVA indicated a significant effect of OA on the rate of DA metabolism, presented as the ratio [homovanillic acid (HVA)]/[DA] in the STR and nucleus accumbens (NAc) (Figures 1K,L and Supplementary Table S1) but no effects were observed in FCx and HC (Figures 1I,J)
Summary
According to the International Association for the Study of Pain (IASP), pain is defined as a complicated phenomenon compromising an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Pain is a crucial evolutionary mechanism designed for the survival of organisms. Long-lasting noxious stimulation is no longer serving its evolutionary role and turning into an unbearable experience. Pain chronification involves structural and functional changes in the central nervous system (Apkarian et al, 2013; Mansour et al, 2013). Accumulating evidence has demonstrated that structures engaged in reward circuits are involved in the transition from acute to chronic pain (Baliki et al, 2012; Vachon-Presseau et al, 2016). Recent work from Martikainen et al (2015)
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