title: Overriding the blockade of antinociceptive actions of opioids in rats treated with extended-release naltrexone.
abstract: A monthly extended-release formulation of the opioid antagonist naltrexone (XR-NTX) is approved for treatment of alcohol dependence. There is little research regarding overriding chronic (>21 days) competitive opioid receptor blockade with opioids for acute pain. Using the hot plate test after XR-NTX or placebo microsphere administration, rats were treated with an opioid analgesic to determine the dose required to produce the maximum response latency (MRL; 60 s). Rats were later treated with the same opioid to determine any potential effects on respiration rate or locomotor activity. In naïve rats, 15 mg/kg morphine, 0.1 mg/kg fentanyl and 8 mg/kg hydrocodone produced MRL. In XR-NTX treated rats, morphine produced 36% and 46% MRL at 90 mg/kg on days 4 and 19 and 96% MRL at 45 mg/kg on day 39. Fentanyl produced 100% MRL at 2.0 mg/kg on days 4 and 19 and at 0.5 mg/kg on day 39. Hydrocodone (80 mg/kg) produced 69%, 80% and 100% MRL on days 4, 19 and 39. Compared to placebo, these doses did not further depress respiration or alter locomotor activity. Thus, opioid receptor blockade with XR-NTX can be overcome in rats with higher doses of opioids without further affecting respiration or locomotor activity.
authors.affiliation: Department of Life Sciences and Toxicology, Alkermes, Inc., 88 Sidney St., Cambridge, MA 02139, USA. reggie.dean@alkermes.com
authors.forename: Reginald L
authors.initials: RL
authors.lastname: Dean
authors.forename: Mark S
authors.initials: MS
authors.lastname: Todtenkopf
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Deaver
authors.forename: Mahin F
authors.initials: MF
authors.lastname: Arastu
authors.forename: Nan
authors.initials: N
authors.lastname: Dong
authors.forename: Krystal
authors.initials: K
authors.lastname: Reitano
authors.forename: Kevin
authors.initials: K
authors.lastname: O'Driscoll
authors.forename: Kristina
authors.initials: K
authors.lastname: Kriksciukaite
authors.forename: David R
authors.initials: DR
authors.lastname: Gastfriend
mesh_terms: D000437:Alcoholism / Q000188:drug therapy; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects; D000818:Animals; D003692:Delayed-Action Preparations; D004347:Drug Interactions; D005283:Fentanyl / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D006853:Hydrocodone / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects; D009043:Motor Activity / Q000187:drug effects; D009271:Naltrexone / Q000008:administration & dosage* / Q000097:blood; D009292:Narcotic Antagonists / Q000008:administration & dosage* / Q000097:blood; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D010993:Plethysmography, Whole Body; D051381:Rats; D017207:Rats, Sprague-Dawley; D012119:Respiration / Q000187:drug effects
chemical_list: D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D009292:Narcotic Antagonists; D009271:Naltrexone; D006853:Hydrocodone; D009020:Morphine; D005283:Fentanyl