Amitriptyline, minocycline and maropitant reduce the sevoflurane minimum alveolar concentration and potentiate remifentanil but do not prevent acute opioid tolerance and hyperalgesia in the rat: a randomised laboratory study.
BACKGROUND
The antidepressant amitriptyline, the inhibitor of microglia activation minocycline, and the neurokinin-1 antagonist maropitant have all been used to prevent or treat hyperalgesia and opioid tolerance.


OBJECTIVE
To determine the effect of amitriptyline, minocycline, maropitant, independently or with remifentanil, on the sevoflurane minimum alveolar concentration in rats and whether these drugs may block opioid-induced hyperalgesia and acute opioid tolerance under inhalational anaesthesia.


METHODS
A randomised, laboratory study.


METHODS
Experimental Unit, La Paz University Hospital, Madrid, Spain.


METHODS
One hundred and fourteen adult male Wistar rats.


METHODS
Intraperitoneal administration of amitriptyline (10 and 50  mg  kg-1), minocycline (30 and 100  mg  kg-1), maropitant (10 and 30 mg  kg-1) or isotonic saline, combined with a constant rate intravenous infusion of remifentanil (240 μg  kg-1  h-1) or saline.


METHODS
Sevoflurane minimum alveolar concentration was determined before and after administration of the drugs; acute opioid tolerance was defined as a decreased ability of remifentanil to reduce the minimum alveolar concentration in the short term. In addition, mechanical nociceptive thresholds were determined before and after these treatments. Opioid-induced hyperalgesia was defined as an increase in mechanical nociceptive thresholds after opioid administration.


RESULTS
Amitriptyline, minocycline and maropitant reduced minimum alveolar concentration up to 24 (8)%, 23 (6)% and 15 (5)%, respectively (P <0.001). Remifentanil alone reduced minimum alveolar concentration by 36 (6)% (P <0.001), and in combination with amitriptyline, minocycline and maropitant, the reduction was 76 (9)%, 75 (16)% and 59 (5)%, respectively (P <0.001). An acute tolerance effect (P < 0.01) and a decrease in the mechanical nociceptive thresholds were observed with remifentanil in all groups.


CONCLUSIONS
Amitriptyline, minocycline and maropitant reduced the minimum alveolar concentration and potentiated the remifentanil minimum alveolar concentration reduction but failed to block opioid-induced hyperalgesia and acute opioid tolerance.
From the Department of Animal Medicine and Surgery, Veterinary Faculty, Complutense University of Madrid (UCM), Madrid, Spain (DA, IAGDS), Laboratory of Respiration Physiology, Carlos Chagas Filho Institute of Biophysics, CCS, Federal University of Rio de Janeiro, Rio de Janeiro, Brasil (MA), Department of Clinical Sciences, Veterinary Faculty, Université de Montréal, Saint Hycianthie, Quebec, Canada (JB) and Department of Anaesthesiology and Critical Care, Puerta de Hierro University Hospital, Madrid, Spain (JGF).
Delia
D
Aguado
Mariana
M
Abreu
Javier
J
Benito
Javier
J
García-Fernández
Ignacio A
IA
Gómez de Segura
D000639:Amitriptyline / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000633:toxicity*; D018685:Anesthetics, Inhalation / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance; D006930:Hyperalgesia / Q000139:chemically induced* / Q000503:physiopathology / Q000523:psychology; D008297:Male; D008738:Methyl Ethers / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008911:Minocycline / Q000494:pharmacology*; D059225:Nociception / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010880:Piperidines / Q000633:toxicity*; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011812:Quinuclidines / Q000494:pharmacology*; D011897:Random Allocation; D017208:Rats, Wistar; D000077208:Remifentanil; D000077149:Sevoflurane
D000701:Analgesics, Opioid; D018685:Anesthetics, Inhalation; D008738:Methyl Ethers; D010880:Piperidines; D011812:Quinuclidines; D000639:Amitriptyline; D000077149:Sevoflurane; C518176:maropitant; D008911:Minocycline; D000077208:Remifentanil