Effects of tizanidine administration on precipitated opioid withdrawal signs in rats.
An opioid withdrawal syndrome was precipitated by naloxone administration in rats treated with morphine. The withdrawal caused alteration of several physiological signs. The aim of the study was to investigate whether the altered physiological profiles were modified by utilising tizanidine, an alpha 2 adrenergic receptor agonist which is capable of affecting faecal and urinary excretion, rectal temperature, pain threshold levels and salivation. To induce an opioid withdrawal syndrome, morphine was administered in three daily intraperitoneal injections for four days at doses of 9, 16 and 25 mg/kg (1st day), 25, 25 and 50 mg/kg (2nd day), 50, 50 and 50 mg/kg (3rd day) and 50, 50 and 100 mg/kg (4th day): naloxone was injected (30 mg/kg) i.p. 180 min after the last morphine injection. Tizanidine was administered orally at 0.17, 0.35 and 0.7 mg/kg, 60 min after the last morphine injection. Signs such as faecal and urine excretion, rectal temperature and latency times to thermal stimulus, salivation, jumping and wet dog shakes were affected in different ways by morphine, naloxone, tizanidine and by the combination of these agents. Notably, the administration of tizanidine in rats receiving morphine and naloxone decreased the intensity of certain withdrawal symptoms, including altered excretion of faeces and urine, salivation and wet dog shake behavior. Body temperature levels and nociceptive threshold values were also modified. The effects caused by tizanidine administration may be due to its alpha 2 receptor agonist activity interfering with a mechanism involved in the regulation of these previously mentioned withdrawal symptoms. Thus, the use of this drug may be indicated as a possible control of the acute phase of opioid withdrawal in heroin addicts.
Pinelli
A
A
Department of Pharmacology, Chemotherapy and Medical Toxicology, Milano, Italy.
Trivulzio
S
S
Spezia
R
R
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001526:Behavioral Symptoms / Q000188:drug therapy; D001831:Body Temperature / Q000187:drug effects; D003000:Clonidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D004347:Drug Interactions; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D009293:Opioid-Related Disorders / Q000188:drug therapy* / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology; D010528:Peristalsis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D014554:Urination / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D009125:Muscle Relaxants, Central; D009292:Narcotic Antagonists; D009294:Narcotics; D010276:Parasympatholytics; D009270:Naloxone; C023754:tizanidine; D009020:Morphine; D003000:Clonidine