title: Reversal of morphine tolerance by a compound with NPFF receptor subtype-selective actions.
abstract: Neuropeptide FF (NPFF) modulates opiate actions. It has pro-nociceptive effects, primarily through the NPFF receptor 1 subtype, and anti-nociceptive effects, primarily through the NPFFR2 subtype. AC-263093 is a small l, organic, systemically active molecule that was previously shown to functionally activate NPFFR2, but not NPFFR1. It was hypothesized that AC-263093 would attenuate morphine tolerance. Rats were tested for radiant heat tail-flick latency before and after 5 mg/kg morphine sulfate s.c. They were then rendered morphine-tolerant by continuous subcutaneous infusion of 17.52 mg/kg/day morphine sulfate. On the seventh day of infusion, they were retested for analgesia 10 and 20 min after 5mg/kg morphine sulfate s.c. Tolerance was indicated by reduction of morphine analgesia from the pre-infusion test. Fifty minutes prior to morphine challenge, rats received either 10 mg/kg i.p. AC-263093 or injection vehicle alone. AC-2623093-treated rats had far smaller tolerance scores than control rats. This drug effect was significant, p = 0.015. The same dose of AC-263093 had almost no analgesic effect in non-tolerant, saline-infused rats. In vitro experiments revealed that AC-263093 had equal affinity for NPFFR1 and NPFFR2, and functionally inactivated NPFFR1, in addition to its previously shown ability to activate NPFFR2. Thus, altering the balance between activation of NPFF receptor subtypes may provide one approach to reversing opiate tolerance.
authors.affiliation: University of Houston-Clear Lake, Houston, TX 77058, United States. Electronic address: malin@uhcl.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Malin
authors.affiliation: University of Houston-Clear Lake, Houston, TX 77058, United States.
authors.forename: Mallori M
authors.initials: MM
authors.lastname: Henceroth
authors.affiliation: University of Houston-Clear Lake, Houston, TX 77058, United States.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Izygon
authors.affiliation: University of Houston-Clear Lake, Houston, TX 77058, United States.
authors.forename: Duyen M
authors.initials: DM
authors.lastname: Nghiem
authors.affiliation: University of Houston-Clear Lake, Houston, TX 77058, United States.
authors.forename: Will D
authors.initials: WD
authors.lastname: Moon
authors.affiliation: University of Houston-Clear Lake, Houston, TX 77058, United States.
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Anderson
authors.affiliation: University of Houston-Clear Lake, Houston, TX 77058, United States.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Madison
authors.affiliation: University of Houston-Clear Lake, Houston, TX 77058, United States.
authors.forename: Pilar
authors.initials: P
authors.lastname: Goyarzu
authors.affiliation: ACADIA Pharmaceuticals Inc., 11085 Torreyanna Road, Suite 100, San Diego, CA 92121, United States.
authors.forename: Jian-Nong
authors.initials: JN
authors.lastname: Ma
authors.affiliation: ACADIA Pharmaceuticals Inc., 11085 Torreyanna Road, Suite 100, San Diego, CA 92121, United States.
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Burstein
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004347:Drug Interactions; D004361:Drug Tolerance; D006834:Hydrazines / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D011869:Radioligand Assay; D017207:Rats, Sprague-Dawley; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C000599125:AC-263093; D000701:Analgesics, Opioid; D006834:Hydrazines; D009842:Oligopeptides; D018013:Receptors, Neuropeptide; C083929:neuropeptide FF receptor; D009020:Morphine; C061209:A18Famide
keywords: Morphine tolerance; Neuropeptide FF; Neuropeptide FF receptor; Opiate tolerance; Receptor subtype; Tail flick