title: Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine.
abstract: Opioids acting at the mu opioid receptor (MOR) are the most effective analgesics, however adverse side effects severely limit their use. Of particular importance, abuse liability results in major medical, societal, and economic problems, respiratory depression is the cause of fatal overdoses, and tolerance complicates treatment and increases the risk of side effects. Motor and cognitive impairment are especially problematic for older adults. Despite the host of negative side effects, opioids such as morphine are commonly used for acute and chronic pain conditions. Separation of analgesia from unwanted effects has long been an unmet goal of opioid research. Novel MOR agonist structures may prove critical for greater success. Here we tested metabolically stable analogs of the endomorphins, endogenous opioids highly selective for the MOR. Compared to morphine, the analogs showed dramatically improved analgesia-to-side-effect ratios. At doses providing equal or greater antinociception than morphine in the rat, the analogs showed reduced a) respiratory depression, b) impairment of motor coordination, c) tolerance and hyperalgesia, d) glial p38/CGRP/P2X7 receptor signaling, and e) reward/abuse potential in both conditioned place preference and self-administration tests. Differential effects on glial activation indicate a mechanism for the relative lack of side effects by the analogs compared to morphine. The results suggest that endomorphin analogs described here could provide gold standard pain relief mediated by selective MOR activation, but with remarkably safer side effect profiles compared to opioids like morphine.
authors.affiliation: SE LA Veterans Affairs Health Care System, Tulane University School of Medicine, New Orleans, LA 70112, USA; Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA; Neuroscience Program, Tulane University School of Medicine, New Orleans, LA 70112, USA; Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA 70112, USA. Electronic address: jzadina@tulane.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Zadina
authors.affiliation: Neuroscience Program, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Nilges
authors.affiliation: Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Morgenweck
authors.affiliation: SE LA Veterans Affairs Health Care System, Tulane University School of Medicine, New Orleans, LA 70112, USA; Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: SE LA Veterans Affairs Health Care System, Tulane University School of Medicine, New Orleans, LA 70112, USA; Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Hackler
authors.affiliation: SE LA Veterans Affairs Health Care System, Tulane University School of Medicine, New Orleans, LA 70112, USA; Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Melita B
authors.initials: MB
authors.lastname: Fasold
mesh_terms: D000701:Analgesics, Opioid / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects; D004361:Drug Tolerance; D004409:Dyskinesia, Drug-Induced / Q000503:physiopathology*; D006930:Hyperalgesia / Q000139:chemically induced / Q000523:psychology; D008262:Macrophage Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D009020:Morphine / Q000633:toxicity*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000187:drug effects; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000503:physiopathology; D019966:Substance-Related Disorders / Q000523:psychology*
chemical_list: D000701:Analgesics, Opioid; C485765:Oprm1 protein, rat; D017450:Receptors, Opioid, mu; D009020:Morphine
keywords: Addiction; Glia; Immunohistochemistry; Opioid; Pain; Reward