Arizona Health Sciences

Spinal or systemic TY005, a peptidic opioid agonist/neurokinin 1 antagonist, attenuates pain with reduced tolerance.

TitleSpinal or systemic TY005, a peptidic opioid agonist/neurokinin 1 antagonist, attenuates pain with reduced tolerance.
Publication TypeJournal Article
Year of Publication2010
AuthorsLargent-Milnes TM, Yamamoto T, Nair P, Moulton JW, Hruby VJ, Lai J, Porreca F, Vanderah TW
JournalBr J Pharmacol
Volume161
Issue5
Pagination986-1001
Date Published2010 Nov
ISSN1476-5381
KeywordsAnalgesics, Opioid, Animals, Behavior, Animal, Disease Models, Animal, Dose-Response Relationship, Drug, Drug Tolerance, Injections, Intravenous, Injections, Spinal, Male, Motor Skills, Neuralgia, Neurokinin-1 Receptor Antagonists, Oligopeptides, Pain Measurement, Rats, Rats, Sprague-Dawley, Receptors, Opioid
Abstract

BACKGROUND AND PURPOSE: The use of opioids in treating pain is limited due to significant side effects including somnolence, constipation, analgesic tolerance, addiction and respiratory depression. Pre-clinical studies have shown that neurokinin 1 (NK(1) ) receptor antagonists block opioid-induced antinociceptive tolerance and may inhibit opioid-induced rewarding behaviours. Here, we have characterized a bifunctional peptide with both opioid agonist and NK(1) antagonist pharmacophores in a rodent model of neuropathic pain.

EXPERIMENTAL APPROACH: Rats were evaluated for behavioural responses to both tactile and thermal stimuli in either an uninjured, sham- or nerve-injured state. TY005 (Tyr-DAla-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bn(CF(3) )(2) ) was delivered spinally or systemically to assess the antinociceptive effects after acute exposure. Motor skills were evaluated using the rotarod test to determine potential sedative effects. Spinal TY005 was given chronically to sham- or nerve-injured animals to determine the development of tolerance.

KEY RESULTS: Bolus injections of TY005 produced dose-dependent antinociception in non-injured animals and alleviated nerve injury-induced thermal and tactile hypersensitivities (i.e. antihyperalgesia) more effectively than morphine. Sedative effects were not evident from the rotarod test at doses that were antihyperalgesic, nor at doses threefold higher. Repeated administration of TY005 did not lead to the development of antihyperalgesic tolerance or alter sensory thresholds.

CONCLUSIONS AND IMPLICATIONS: Collectively, the data suggest that opioid agonist/NK(1) antagonist bifunctional peptides represent a promising novel approach to the management of chronic pain without the development of tolerance, reducing the need for escalation of doses and unwanted side effects associated with opiates alone.

DOI10.1111/j.1476-5381.2010.00824.x
Alternate JournalBr. J. Pharmacol.
PubMed ID20977451
PubMed Central IDPMC2998681
Grant ListP01 DA006284 / DA / NIDA NIH HHS / United States
R01 DA013449 / DA / NIDA NIH HHS / United States
DA06284 / DA / NIDA NIH HHS / United States
DA13449 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Tally Largent-Milnes, Ph.D.
Frank Porreca, Ph.D.
Todd Vanderah, Ph.D.