Arizona Health Sciences

Oxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated mu-opioid receptor-Gs coupling.

TitleOxycodone plus ultra-low-dose naltrexone attenuates neuropathic pain and associated mu-opioid receptor-Gs coupling.
Publication TypeJournal Article
Year of Publication2008
AuthorsLargent-Milnes TM, Guo W, Wang H-Y, Burns LH, Vanderah TW
JournalJ Pain
Volume9
Issue8
Pagination700-13
Date Published2008 Aug
ISSN1528-8447
KeywordsAdministration, Oral, Analgesics, Opioid, Animals, Behavior, Animal, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Therapy, Combination, Hyperalgesia, Injections, Spinal, Male, Naltrexone, Narcotic Antagonists, Neuralgia, Oxycodone, Pain Threshold, Rats, Rats, Sprague-Dawley, Receptors, G-Protein-Coupled, Receptors, Opioid, mu, Signal Transduction, Spinal Nerves
Abstract

UNLABELLED: Both peripheral nerve injury and chronic opioid treatment can result in hyperalgesia associated with enhanced excitatory neurotransmission at the level of the spinal cord. Chronic opioid administration leads to a shift in mu-opioid receptor (MOR)-G protein coupling from G(i/o) to G(s) that can be prevented by cotreatment with an ultra-low-dose opioid antagonist. In this study, using lumbar spinal cord tissue from rats with L(5)/L(6) spinal nerve ligation (SNL), we demonstrated that SNL injury induces MOR linkage to G(s) in the damaged (ipsilateral) spinal dorsal horn. This MOR-G(s) coupling occurred without changing G(i/o) coupling levels and without changing the expression of MOR or Galpha proteins. Repeated administration of oxycodone alone or in combination with ultra-low-dose naltrexone (NTX) was assessed on the SNL-induced MOR-G(s) coupling as well as on neuropathic pain behavior. Repeated spinal oxycodone exacerbated the SNL-induced MOR-G(s) coupling, whereas ultra-low-dose NTX cotreatment slightly but significantly attenuated this G(s) coupling. Either spinal or oral administration of oxycodone plus ultra-low-dose NTX markedly enhanced the reductions in allodynia and thermal hyperalgesia produced by oxycodone alone and minimized tolerance to these effects. The MOR-G(s) coupling observed in response to SNL may in part contribute to the excitatory neurotransmission in spinal dorsal horn in neuropathic pain states. The antihyperalgesic and antiallodynic effects of oxycodone plus ultra-low-dose NTX (Oxytrex, Pain Therapeutics, Inc., San Mateo, CA) suggest a promising new treatment for neuropathic pain.

PERSPECTIVE: The current study investigates whether Oxytrex (oxycodone with an ultra-low dose of naltrexone) alleviates mechanical and thermal hypersensitivities in an animal model of neuropathic pain over a period of 7 days, given locally or systemically. In this report, we first describe an injury-induced shift in mu-opioid receptor coupling from G(i/o) to G(s), suggesting why a mu-opioid agonist may have reduced efficacy in the nerve-injured state. These data present a novel approach to neuropathic pain therapy.

DOI10.1016/j.jpain.2008.03.005
Alternate JournalJ Pain
PubMed ID18468954
PubMed Central IDPMC5469510
Grant ListR01 DA015205 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, Ph.D.
Todd Vanderah, Ph.D.