Is the reduced efficacy of morphine in diabetic rats caused by alterations of opiate receptors or of morphine pharmacokinetics?
Because it generally is admitted that neuropathic pain is resistant to opioid analgesia, we investigated the effect of morphine on hyperalgesia in streptozocin-induced diabetes in rats. The antinociceptive effect of morphine (0.5-4 mg/kg i.v.) on mechanical (paw pressure test), thermal (tail immersion test) and chemical (formalin test) hyperalgesia was reduced. To clarify the mechanisms involved in the alteration of morphine analgesia, the binding characteristics of mu and delta receptor agonists and the pharmacokinetics of morphine and its glucuronide metabolites morphine 3-glucuronide and morphine 6-glucuronide were determined. KD and Bmax values for [3H][D-Ala2,(Me)Phe4, Gly(ol)5]enkephalin and [3H][D-Pen2,D-Pen5]enkephalin to cerebral mu and delta opiate receptors were not altered by diabetes. Likewise, the plasma maximal concentration of morphine and metabolites, as well as the area under the curve, did not differ between diabetic and normal rats. Only the total clearance and the apparent volume of distribution of morphine were increased in diabetic rats, which suggests that the diabetes-induced glycosylation of proteins might increase the distribution of morphine in the aqueous compartment. These data indicate that the reduced analgesic effect of morphine caused by diabetes cannot be explained by a decrease in opiate-receptor affinity or density but rather by kinetic alteration of morphine (increase of total clearance and of volume of distribution in comparison with healthy animals).
Courteix
C
C
Equipe NPPUA, Laboratoire de Pharmacologie, Faculté de Pharmacie, F-63001 Clermont-Ferrand Cedex, France.
Bourget
P
P
Caussade
F
F
Bardin
M
M
Coudore
F
F
Fialip
J
J
Eschalier
A
A
D000698:Analgesia; D000700:Analgesics / Q000493:pharmacokinetics; D000701:Analgesics, Opioid / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000378:metabolism / Q000493:pharmacokinetics*; D010147:Pain Measurement; D017288:Pain Threshold; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013311:Streptozocin
D000700:Analgesics; D000701:Analgesics, Opioid; D004745:Enkephalins; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D013311:Streptozocin; D009020:Morphine; D020881:Enkephalin, D-Penicillamine (2,5)-