Quantitative evaluation of opioid withdrawal signs in rats repeatedly treated with morphine and injected with naloxone, in the absence or presence of the antiabstinence agent clonidine.
An opioid withdrawal syndrome was induced in rats by repeated morphine administration and final naloxone injection. The withdrawal causes alteration of several physiological signs. The aim of the study was to describe a quantitative opioid abstinence syndrome to validate the methodology by utilizing clonidine, a well-known antiwithdrawal agent, and propose the procedure for the screening of antiabstinence drugs. In particular, rats were treated with saline, morphine, naloxone, morphine and naloxone and four doses of clonidine (0, 0.04, 0.1, and 0.25 mg/kg orally). In rats repeatedly exposed to morphine and then injected with naloxone, signs like excretion of feces and urine, salivation, behavioral jumping and wet dog shakes, rectal temperature, and pain threshold have been observed. Consequently, the objective symptoms observed in morphine plus naloxone-treated animals have been taken as markers of opioid withdrawal. These factors have been quantitatively measured and grouped to form a standardized procedure of opioid abstinence syndrome. In addition, it is possible to observe that the antiabstinence drug clonidine exerted effects on modified physiological signs appearing in morphine-dependent rats treated with naloxone, like fecal excretion, levels of rectal temperature, latency times, salivation as well as jumping behavior. The effects exerted by clonidine in this procedure and in other methods are compared and appear to be similar. In addition, comparative observations referring to both the previous methods and the present procedure related to the type of signs studied, the modality of evaluation, and suppressive activity exerted by the antiwithdrawal agent, clonidine, are performed: the greater accuracy of the proposed method becomes apparent. Thus, this experimental model, validated by the antiabstinence agent clonidine, is proposed as a useful screen for drugs affecting opioid withdrawal syndrome.
Pinelli
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A
Department of Pharmacology, Chemotherapy and Medical Toxicology, Milano, Italy.
Trivulzio
S
S
D000284:Administration, Oral; D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D003000:Clonidine / Q000627:therapeutic use*; D003672:Defecation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects*; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D009294:Narcotics / Q000008:administration & dosage / Q000009:adverse effects*; D017288:Pain Threshold / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012472:Salivation / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000503:physiopathology* / Q000652:urine; D014554:Urination / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D009292:Narcotic Antagonists; D009294:Narcotics; D009270:Naloxone; D009020:Morphine; D003000:Clonidine