The Downregulation of Opioid Receptors and Neuropathic Pain

Abstract

Neuropathic pain (NP) refers to pain caused by primary or secondary damage or dysfunction of the peripheral or central nervous system, which seriously affects the physical and mental health of 7–10% of the general population. The etiology and pathogenesis of NP are complex; as such, NP has been a hot topic in clinical medicine and basic research for a long time, with researchers aiming to find a cure by studying it. Opioids are the most commonly used painkillers in clinical practice but are regarded as third-line drugs for NP in various guidelines due to the low efficacy caused by the imbalance of opioid receptor internalization and their possible side effects. Therefore, this literature review aims to evaluate the role of the downregulation of opioid receptors in the development of NP from the perspective of dorsal root ganglion, spinal cord, and supraspinal regions. We also discuss the reasons for the poor efficacy of opioids, given the commonness of opioid tolerance caused by NP and/or repeated opioid treatments, an angle that has received little attention to date; in-depth understanding might provide a new method for the treatment of NP.

Neuromodulation and Habituation: A Literature Review and Conceptional Analysis of Sustaining Therapeutic Efficacy and Mitigating Habituation

“…Per the United States Food and Drug Administration guidelines, a patient is considered tolerant to opioids at doses greater than 60 mg morphine equivalents (MME) per day [65]. As summarized in Li et al, mechanisms contributing to opioid tolerance include increased drug metabolism, the compensatory/opposing process, and the downregulation of opioid receptors [66].…”

The psychophysiology of music-based interventions and the experience of pain

“…In animal studies, analgesic effects of oxytocin have been described after experimentally induced acute (Rash et al, 2014), neuropathic and inflammatory pain experiences (Yu et al, 2003;Condes-Lara et al, 2005;Eliava et al, 2016;Sun et al, 2018;Hilfiger et al, 2020;Li et al, 2021;Esmaeilou et al, 2022;Nishimura et al, 2022;Iwasaki et al, 2023;Krabichler and Reynders, 2023;Li Y.-J. et al, 2023;, and increased expression of oxytocin receptors has been reported after chemotherapy-induced neuropathic pain in mice (Li et al, 2023a). Similar to the distribution of oxytocin receptors in the CNS (Insel and Shapiro, 1992;Quintana et al, 2019) the anatomical location of these oxytocinergic effects is widespread, although in mice at least, there is not always congruence between oxytocin output and receptor expression (Son et al, 2022).…”

Novel Drug Targets and Emerging Pharmacotherapies in Neuropathic Pain

“…Pharmaceutics 2023, 15, x FOR PEER REVIEW 3 and may limit the long-term efficacy of opioid-based therapies in treating neurop pain [14][15][16][17]. The endocannabinoid system, which consists of the cannabinoid receptors CB1 CB2, along with endogenous ligands (endocannabinoids), plays a modulatory role in perception [18][19][20][21].…”

“…Opioid receptors, including mu, delta, and kappa receptors, are distributed throughout the nervous system and are involved in pain modulation [ 14 , 15 , 16 , 17 ]. Endogenous opioids, such as endorphins and enkephalins, bind to opioid receptors to inhibit pain transmission.…”

“…Endogenous opioids, such as endorphins and enkephalins, bind to opioid receptors to inhibit pain transmission. In neuropathic pain, alterations in opioid receptor expression and function can occur, resulting in reduced endogenous opioid effectiveness and diminished response to exogenous opioids, leading, in turn, to decreased pain relief [ 14 , 15 , 16 , 17 ]. Opioid receptor desensitization and downregulation contribute to the development of opioid tolerance and may limit the long-term efficacy of opioid-based therapies in treating neuropathic pain [ 14 , 15 , 16 , 17 ].…”