Quantitative opioid withdrawal signs in rats: effects exerted by clothiapine administration

An opioid withdrawal syndrome, which causes alteration of several physiological signs, was induced in rats by repeated morphine administration and final naloxone injection. The aim of this study was prevention of the altered physiological profiles by utilising clothiapine, which is capable of affecting fecal and urinary excretion, rectal temperature, pain threshold levels and salivatory behaviour. Morphine was administered in three daily intraperitoneal (ip) injections for 4 days at doses of 9, 16 and 25 mg/kg (d 1), 25, 25 and 50 mg/kg (d 2), 50, 50 and 50 mg/kg (d 3) and 50, 50 and 100 mg/kg (d 4). Naloxone was injected (30 mg/kg) ip 180 min after the last morphine injection. Clothiapine was administered orally 0.7, 2 and 6 mg/kg 2 hours before the naloxone administration. Signs such as fecal 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, clothiapine and combination of them. Notably the administration of clothiapine in rats receiving morphine and naloxone decreased the intensity of certain withdrawal symptoms, such as altered excretion of feces, temperature values, salivation, jumping and wet dog shakes behaviour, and elevated the nociceptive threshold values. The effects exhibited by clothiapine administration may be explained through its antimuscarinic, antiadrenergic and antidopaminergic activities interfering with the mechanisms involved in the regulation of these previously mentioned withdrawal symptoms. The use of this drug is thus suggested as a possible control of the acute phase of opioid withdrawal in heroin addicts.