title: Nitroglycerin inhibits the development of morphine tolerance and dependence in rats.
abstract: The development of tolerance to and physical dependence on opioids remains a significant barrier to their clinical use. N-Methyl-D-aspartate (NMDA) receptor antagonists inhibit tolerance and dependence. However, many NMDA antagonists have undesirable side effects. It has been shown that nitroglycerin (NTG) can antagonize NMDA receptor activity. This study was designed to determine whether NTG could inhibit the development of morphine tolerance and dependence. Rats were anesthetized and implanted with either morphine or placebo pellets, and pumps infusing vehicle or NTG (doses from 0.1 microg/kg/day to 10 mg/kg/day). Tolerance development was assessed by tail-flick latency (TFL). After 6 days, withdrawal was precipitated by subcutaneous injection of 2 mg/kg naloxone. Withdrawal signs were observed for 15 min. Placebo-pelleted rats showed no changes in TFL over the course of the study and no withdrawal signs. Morphine-pelleted rats developed tolerance. The 0.1 mg/kg/day NTG dose significantly attenuated tolerance development, while the other doses had no significant effect. The 0.1 mg/kg/day dose also attenuated some withdrawal signs. Higher or lower doses were not effective, possibly because of competing biochemical effects.
authors.affiliation: Department of Anesthesiology, UT-MD Anderson Cancer Center, 1515 Holcombe Blvd., Box 110, Houston, TX 77030-4009, USA.
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Cha
authors.forename: Lionel
authors.initials: L
authors.lastname: Moulédous
authors.forename: J Robin
authors.initials: JR
authors.lastname: Harris
authors.forename: Mark A
authors.initials: MA
authors.lastname: Weech
authors.forename: Howard B
authors.initials: HB
authors.lastname: Gutstein
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology*; D015918:Infusion Pumps, Implantable; D008297:Male; D009021:Morphine Dependence / Q000517:prevention & control* / Q000523:psychology; D005996:Nitroglycerin / Q000008:administration & dosage*; D010147:Pain Measurement / Q000187:drug effects* / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D005996:Nitroglycerin