title: Analgesic synergy of neurotensin receptor subtype 2 agonist NT79 and morphine.
abstract: Neurotensin (NT) is a tridecapeptide with naloxone-independent analgesic action. NT exerts its effects through three molecularly cloned receptor subtypes, NTS1, NTS2, and NTS3. The analgesic efficacy of NT agonists depends on their activation of NTS1 and/or NTS2. NT79 is an NTS2-selective agonist without hypothermic and hypotensive effects, produces analgesic effects in animal models of visceral (writhing), but not thermal (hot plate) pain. This study extends previous study with NT79 to test its efficacy in an animal model of persistent pain (formalin test) and to determine whether there is analgesic synergy between NT79 and morphine on visceral and persistent pain. NT79 enhanced the analgesic potency of morphine in the writhing test. In the persistent pain model, NT79 and morphine attenuated formalin-induced lifting and biting during the inflammatory phase. NT79 and morphine alone significantly blocked the lifting but not the biting response, which involves the activity of spinal nociceptive circuits. However, the combination of NT79 and morphine attenuated both lifting and biting responses, results indicating both spinal and supraspinal modulation of persistent nociception. Isobolographic analyses show analgesic synergism between NT79 and morphine in persistent pain, thus providing a promise of therapy for pain while minimizing adverse effects associated with morphine use.
authors.affiliation: Neuropsychopharmacology Laboratory, Mayo Foundation for Medical Education and Research, Mayo Clinic, Jacksonville, Florida 32224, USA. boules.mona@mayo.edu
authors.forename: Mona
authors.initials: M
authors.lastname: Boules
authors.forename: Hannah
authors.initials: H
authors.lastname: Johnston
authors.forename: Jessica
authors.initials: J
authors.lastname: Tozy
authors.forename: Kristin
authors.initials: K
authors.lastname: Smith
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Li
authors.forename: Elliott
authors.initials: E
authors.lastname: Richelson
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004357:Drug Synergism; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009496:Neurotensin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018028:Receptors, Neurotensin / Q000819:agonists*
chemical_list: D000701:Analgesics, Opioid; C099727:Ntsr2 protein, rat; D010446:Peptide Fragments; D018028:Receptors, Neurotensin; C547346:neurotensin NT79; D009496:Neurotensin; D009020:Morphine