Peripherally Acting Opioids in Orofacial Pain

The activation of opioid receptors by exogenous or endogenous opioids can produce significant analgesic effects in peripheral tissues. Numerous researchers have demonstrated the expression of peripheral opioid receptors (PORs) and endogenous opioid peptides (EOPs) in the orofacial region. Growing evidence has shown the involvement of PORs and immune cell-derived EOPs in the modulation of orofacial pain. In this review, we discuss the role of PORs and EOPs in orofacial pain and the possible cellular mechanisms involved. Furthermore, the potential development of therapeutic strategies for orofacial pain is also summarized.

Structural Insights Accelerate the Discovery of Opioid Alternatives

Opioids such as morphine and oxycodone are analgesics frequently prescribed for the treatment of moderate or severe pain. Unfortunately, these medications are associated with exceptionally high abuse potentials and often cause fatal side effects, mainly through the μ-opioid receptor (MOR). Efforts to discover novel, safer, and more efficacious analgesics targeting MOR have encountered challenges. In this review, we summarize alternative strategies and targets that could be used to develop safer nonopioid analgesics. A molecular understanding of G protein–coupled receptor activation and signaling has illuminated not only the complexities of receptor pharmacology but also the potential for pathway-selective agonists and allosteric modulators as safer medications. The availability of structures of pain-related receptors, in combination with high-throughput computational tools, has accelerated the discovery of multitarget ligands with promising pharmacological profiles. Emerging clinical evidence also supports the notion that drugs targeting peripheral opioid receptors have potential as improved analgesic agents. Expected final online publication date for the Annual Review of Biochemistry, Volume 90 is June 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Involvement of Peripheral Opioid Receptors in the Realization of Food Motivation Into Eating Behavior

The involvement of peripheral opioid receptors in the mechanisms of eating behavior is still unclear. The aim of this work was to study the role of peripheral, predominantly gastric mu and delta opioid receptors in the realization of food motivation in conditions of different energy costs for eating behavior. Experiments were performed under a between-sessions progressive ratio schedule of reinforcement in food-deprived rats. The level of food motivation was calculated using a self-developed method. Food intake, motor activity, and metabolic rate were recorded in fed and hungry animals. Results showed that intragastric administration of the mu opioid receptor agonist DAMGO led to an increase in the level of food motivation in the light variant of operant feeding behaviors. Food consumption did not change. At high costs for feeding behavior, the administration of DAMGO did not alter food motivation; however, food consumption and motor activity were reduced. Intragastric administration of the delta opioid receptor agonist DADLE did not lead to changes in the level of food motivation and physical activity, but inhibition of feeding behavior was observed in all reinforcement schedules. Three regulatory pathways of eating behavior in difficult food conditions by peripheral, predominantly gastric opioid receptors are hypothesized: environmental-inhibitory afferentations and suppression of the realization of food motivation into behavior; homeostatic-inhibitory action on food motivation; and rewarding-suppression of the anticipatory reinforcement.

On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance

There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, β-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance.