Search for the “ideal analgesic” in pain treatment by engineering the mu‐opioid receptor

Abstract

SummaryThe myriad of side effects that associate with morphine has been problematic in the clinical use to manage moderate to severe pain. It has been the holy grail of the pharmacologists to develop a compound, or treatment paradigm that could retain the analgesic effect of the drug as eliminating or reducing the side effects, mainly the tolerance and addiction development associates with chronic usage of the drug. In our earlier receptor structure/activities studies, we discovered an unique mutation of a conserved Ser in the fourth transmembrane domain of the opioid receptor that the alkaloid antagonist could activate the receptor. On the basis of this initial finding, we decide to explore the possibility of using virus to deliver the mutant muopioid receptor at the various sites of the nociceptive pathway and induce the antinociceptive responses with the systemic administration of opioid antagonists. In this article, we will summarize the progress of such approach and the probable advantages over the conventional approach of drug development in the treatment of chronic pain.

Convallatoxin enhance the ligand-induced mu-opioid receptor endocytosis and attenuate morphine antinociceptive tolerance in mice

“…Opioids have long been used to treat severe pain 1 . However, long-term use leads to tolerance, dependence and addiction 2 . No currently available drugs can completely substitute for opioids in most clinical opioid indications, and no treatment paradigms can successfully prevent the development of tolerance and addiction.…”

Synthesis and Investigation of Mixed μ‐Opioid and δ‐Opioid Agonists as Possible Bivalent Ligands for Treatment of Pain

“…Several studies indicate that δ‐receptor agonists as well as δ‐receptor antagonists provide significant modulation of the pharmacological effects of μ‐agonists. It has been shown that agonists at the δ‐receptor can enhance the analgesic potency and efficacy of μ‐agonists while δ‐antagonists can prevent or diminish the development of tolerance and physical dependence by μ‐agonists; multiple and controversial interpretations of the observed phenomena have been made .…”

Naloxone reversal of an overdose of a novel, long‐acting transdermal fentanyl solution in laboratory Beagles

“…Many strategies have been pursued to identify technologies that meet these characteristics. At the drug discovery level, attempts have been made to identify an ideal analgesic by engineering the mu‐opioid receptor (Tao et al. , 2010).…”

“…Many strategies have been pursued to identify technologies that meet these characteristics. At the drug discovery level, attempts have been made to identify an ideal analgesic by engineering the mu-opioid receptor (Tao et al, 2010). Others have concentrated on ways to alter existing analgesics or to combine existing analgesic compounds with drugs that may improve effectiveness while minimizing adverse effects (Smith, 2008).…”