Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability

Abstract

Recent preclinical and clinical studies have demonstrated that cotreatments with extremely low doses of opioid receptor antagonists can markedly enhance the efficacy and specificity of morphine and related opioid analgesics. Our correlative studies of the cotreatment of nociceptive types of dorsal-root ganglion neurons in vitro and mice in vivo with morphine plus specific opioid receptor antagonists have shown that antagonism of Gs-coupled excitatory opioid receptor functions by cotreatment with ultra-low doses of clinically available opioid antagonists, e.g. naloxone and naltrexone, markedly enhances morphine's antinociceptive potency and simultaneously attenuates opioid tolerance and dependence. These preclinical studies in vitro and in vivo provide cellular mechanisms that can readily account for the unexpected enhancement of morphine's analgesic potency in recent clinical studies of post-surgical pain patients cotreated with morphine plus low doses of naloxone or nalmefene. The striking consistency of these multidisciplinary studies on nociceptive neurons in culture, behavioral assays on mice and clinical trials on post-surgical pain patients indicates that clinical treatment of pain can, indeed, be significantly improved by administering morphine or other conventional opioid analgesics together with appropriately low doses of an excitatory opioid receptor antagonist.

Molecular Changes in Opioid Addiction: The Role of Adenylyl Cyclase and cAMP/PKA System

“…This conversion from inhibitory G i/o to stimulatory G s via GM 1 ganglioside phosphorylation may be one of the underlying mechanisms for the development of opioid dependence. 43 Furthermore, we have previously shown that this shift may also enhance the toxic effects of morphine. Morphine-induced antinociception was reduced but seizure-like activity increased in mice treated intracerebroventricularly with PTX (ADP-ribosylates the inhibitory G proteins).…”

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

“…24,41,42,45,[47][48][49]58 Chronic opioid use has been shown paradoxically to cause excitatory rather than inhibi tory effects on the cell, stimulating pain propagation. 11,14,26,27,31,40,67,76 Remarkably, cotreatment with ultra-low-dose naloxone, an opioid antagonist, prevents the shift in G protein coupling by the MOR as well as the analgesic tolerance and dependence induced by chronic opioid treatment. 74 Recent data have revealed that a 4-picomolar interaction between the opioid antagonists naloxone or naltrexone (NTX) and the MORinteracting scaffolding protein filamin A is responsible for the prevention of MOR's G protein coupling switch 73 rather than their direct interaction with opioid receptors that occurs at much higher doses.…”

“…24,41,42,45,[47][48][49]58 Chronic opioid use has been shown paradoxically to cause excitatory rather than inhibi tory effects on the cell, stimulating pain propagation. 11,14,26,27,31,40,67,76 This enhanced pain and the underlying excitatory signaling have been proposed to be mediated by opioid receptors preferentially coupling to G s proteins, 19,60 or alternatively, via the Gβγ dimer of the G i/o proteins native to opioid receptors. 36,76 More recent data have shown that chronic opioid administration leads to a shift in G protein coupling by μ-opioid receptors (MOR) from G i/o to G s, 74 with the Gβγ of this MOR-associated G s protein also contributing to the excitatory signaling.…”

Influence of naloxone on quality and duration of analgesia produced by thoracic epidural morphine and bupivacaine

“…All patients were premedicated with fentanyl 1 µg/kg i.v. After placement of epidural catheter at T [6][7][8] interspaces, all patients were administered morphine 0.1mg/kg with 0.125% bupivacaine immediately before induction of general anaesthesia. VAS was assessed immediately after extubation and a bolus dose of 0.01mg/kg epidural morphine was administered when VAS exceeded 3 in postoperative follow up period of 72hrs in all patients.…”

“…5 Controlled trials in children and adolescents show that small-dose naloxone infusions (0.25µg/kg/hour) can significantly reduce opioid-induced side effects without affecting analgesia. 6 Another study shows that low dose naloxone (0.25µg/kg/hour) significantly reduces the patient controlled analgesia (PCA) cumulative morphine consumption during the first 24 hours postoperatively and incidence of postoperative nausea and vomiting (PONV) and pruritus were also significantly reduced. Patients receiving a higher dose of naloxone (1µg/kg/hour) experience a reduction in PONV and pruritus but consume similar amounts of morphine compared with patients in the placebo group.…”