Chronic infusion of clonidine does not alleviate spontaneous morphine withdrawal symptoms in rats.
Opiate withdrawal is associated with behavioural symptoms and a sympathetic hyperactivity, the latter being sensitive to clonidine. The central question is whether behavioural symptoms would be also sensitive to clonidine. A rat model was used in which the locomotor activity was measured 24 h a day during the morphine withdrawal phase. Spontaneous withdrawal of morphine reduced strongly the high nocturnal locomotor activity, concomitantly decreasing food intake and body weight. Chronic infusion of clonidine (30-120 micrograms/kg/day) using osmotic minipumps had no effect on the withdrawal symptoms. Higher dosages (250-1000 micrograms/kg/day) potentiated rather than alleviated the withdrawal symptoms, suggesting an alpha 1-adrenergic effect of clonidine rather than an alpha 2-action. Therefore, we studied the action of a more specific alpha 2-agonist UK-14.304. UK-14.304 was less potent than clonidine in naive animals. It slightly alleviates the decrease of nocturnal activity during spontaneous morphine withdrawal. Furthermore, we have tested whether the effects of high dosages of clonidine could be altered by a specific alpha 1-antagonist doxazosine. Doxazosine reduced only slightly the potentiation in the decrease in food intake by clonidine during morphine withdrawal. For the other symptoms no interaction between doxazosine and clonidine was found. The data suggest that the use of clonidine in the detoxification of opiate dependent people is based on the suppression of the sympathetic hyperactivity rather than on symptoms with a more behavioural character.
Laboratory for Medicines and Medical Devices, National Institute for Public Health and Environmental Protection, Bilthoven, The Netherlands.
J W
JW
van der Laan
C
C
Jansen van't Land
D000316:Adrenergic alpha-Agonists / Q000627:therapeutic use; D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use; D000818:Animals; D000068438:Brimonidine Tartrate; D003000:Clonidine / Q000008:administration & dosage / Q000494:pharmacology*; D017292:Doxazosin; D004343:Drug Implants; D004435:Eating / Q000187:drug effects; D005502:Food; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000097:blood; D009021:Morphine Dependence / Q000523:psychology*; D009043:Motor Activity / Q000187:drug effects; D011224:Prazosin / Q000031:analogs & derivatives / Q000627:therapeutic use; D011810:Quinoxalines / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D004343:Drug Implants; D011810:Quinoxalines; D000068438:Brimonidine Tartrate; D009020:Morphine; D003000:Clonidine; D017292:Doxazosin; D011224:Prazosin