Building a better analgesic: multifunctional compounds that address injury-induced pathology to enhance analgesic efficacy while eliminating unwanted side effects.

TitleBuilding a better analgesic: multifunctional compounds that address injury-induced pathology to enhance analgesic efficacy while eliminating unwanted side effects.
Publication TypeJournal Article
Year of Publication2013
AuthorsLargent-Milnes TM, Brookshire SW, Skinner DP, Hanlon KE, Giuvelis D, Yamamoto T, Davis P, Campos CR, Nair P, Deekonda S, Bilsky EJ, Porreca F, Hruby VJ, Vanderah TW
JournalJ Pharmacol Exp Ther
Volume347
Issue1
Pagination7-19
Date Published2013 Oct
ISSN1521-0103
KeywordsAnalgesics, Opioid, Animals, Ferrets, Injections, Intraventricular, Injections, Spinal, Male, Mice, Mice, Inbred ICR, Morphine, Naloxone, Pain, Pain Measurement, Rats, Rats, Sprague-Dawley, Receptors, Neurokinin-1, Spinal Nerves, Treatment Outcome
Abstract

The most highly abused prescription drugs are opioids used for the treatment of pain. Physician-reported drug-seeking behavior has resulted in a significant health concern among doctors trying to adequately treat pain while limiting the misuse or diversion of pain medications. In addition to abuse liability, opioid use is associated with unwanted side effects that complicate pain management, including opioid-induced emesis and constipation. This has resulted in restricting long-term doses of opioids and inadequate treatment of both acute and chronic debilitating pain, demonstrating a compelling need for novel analgesics. Recent reports indicate that adaptations in endogenous substance P/neurokinin-1 receptor (NK1) are induced by chronic pain and sustained opioid exposure, and these changes may contribute to processes responsible for opioid abuse liability, emesis, and analgesic tolerance. Here, we describe a multifunctional mu-/delta-opioid agonist/NK1 antagonist compound [Tyr-d-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bn(CF3)2 (TY027)] that has a preclinical profile of excellent antinociceptive efficacy, low abuse liability, and no opioid-related emesis or constipation. In rodent models of acute and neuropathic pain, TY027 demonstrates analgesic efficacy following central or systemic administration with a plasma half-life of more than 4 hours and central nervous system penetration. These data demonstrate that an innovative opioid designed to contest the pathology created by chronic pain and sustained opioids results in antinociceptive efficacy in rodent models, with significantly fewer side effects than morphine. Such rationally designed, multitargeted compounds are a promising therapeutic approach in treating patients who suffer from acute and chronic pain.

DOI10.1124/jpet.113.205245
Alternate JournalJ. Pharmacol. Exp. Ther.
PubMed ID23860305
PubMed Central IDPMC3781412
Grant ListDA-06284 / DA / NIDA NIH HHS / United States
DA-13449 / DA / NIDA NIH HHS / United States
R01 DA013449 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Peg Davis
Victor Hruby, Ph.D.
Tally Largent-Milnes, PhD
Frank Porreca, PhD
Todd Vanderah, PhD