Crosstalk between Mu-Opioid receptors and neuroinflammation: Consequences for drug addiction and pain

A C T Mu-Opioid Receptors (MORs) are well-known for participating in analgesia, sedation, drug addiction, and other physiological functions.Although MORs have been related to neuroinflammation their biological mechanism remains unclear.It is suggested that MORs work alongside Toll-Like Receptors to enhance the release of proinflammatory mediators and cytokines during pathological conditions.Some cytokines, including TNF-α, IL-1β and IL-6, have been postulated to regulate MORs levels by both avoiding MOR recycling and enhancing its production.In addition, Neurokinin-1 Receptor, also affected during neuroinflammation, could be regulating MOR trafficking.Therefore, inflammation in the central nervous system seems to be associated with altered/ increased MORs expression, which might regulate harmful processes, such as drug addiction and pain.Here, we provide a critical evaluation on MORs' role during neuroinflammation and its implication for these conditions.Understanding MORs' functioning, their regulation and implications on drug addiction and pain may help elucidate their potential therapeutic use against these pathological conditions and associated disorders. Mu-Opioid receptorsMu-Opioid Receptors (MORs) belong to the family of Opioid Receptors (ORs), which are metabotropic receptors well-known for binding opioidergic drugs such as morphine and heroin.Other members of the ORs family include Delta (DOR), Kappa (KOR) and opioid receptor like-1 (ORL1).All ORs can bind with differential affinity distinct endogenous (own produced by the organisms) opioids, including endorphins (recognized by MORs), enkephalins (DORs), dynorphins (KORs) and nociceptins (ORL1) (Bodnar, 2022).ORs also differ in their distribution within the nervous system.MORs, DORs and ORL1 are widespread in the central nervous system (CNS), whereas KORs are more restricted to the midline and ventral structures (Allen Institute for Brain Science, 2011).ORs participate in many processes including analgesia, neuroprotection, respiratory control, ionic homeostasis, peristalsis, mood regulation, cardioprotection and sedation, among others (reviewed elsewhere: Shenoy and Lui, 2018).The effects of endogenous opioids also depend on where in the nervous system they bind their receptors, the cell type they have their effects on, and the specific receptor(s) to which they bind.In particular, they can produce analgesia, euphoria, reinforcement, sedation, dysphoria, miosis, addiction, truncal rigidity, hedonia, aversion, nausea, and reduce the rate of respiration and cough reflex in the CNS (McNicol et al., 2003;Hyman et al., 2006;Le Merrer et al., 2009;Al-Hasani and Bruchas, 2011; Castro and Berridge, 2014a).Interestingly, activation of the different ORs might result in opposite outcomes.Indeed, MORs activation within the mesocorticolimbic system (MCLS) induces euphoria, whereas KORs and DORs activation leads to dysphoric