Abstract
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 andBmax 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).
Footnotes
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Send reprint requests to: C. Courteix, Laboratoire de Pharmacologie, Faculté de Pharmacie, Place H. Dunant BP 38, F-63001 Clermont-Ferrand, France.
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↵1 Current address: Service de Pharmacie Clinique, Institut Gustave-Roussy, 39, rue Camille Desmoulins, F-94805 Villejuif, Cedex France.
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↵2 Current address: Laboratoires UPSA, 128 rue Danton, F-92506 Rueil-Malmaison.
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↵3 Current address: Equipe NPPUA, Laboratoire de Pharmacologie Médicale, Faculté de Médecine, Place H. Dunant, BP 38, F-63001 Clermont-Ferrand Cedex 1.
- Abbreviations:
- AUC
- area under the curve
- Cmax
- maximal concentration
- Cl
- total clearance
- i.v.
- intravenously
- MPE
- maximum possible effect
- MRT
- mean residence time
- M3G
- morphine-3-glucuronide
- M6G
- morphine-6-glucuronide
- S.E.M.
- standard error of the mean
- STZ
- streptozocin
- T1/2
- elimination half-life time
- Tmax
- delay to reachCmax
- Vd
- apparent volume of distribution
- DAMGO
- [d-Ala2,(Me)Phe4,Gly(ol)5]enkephalin
- DPDPE
- [dPen2,d-Pen5]enkephalin
- Received April 29, 1997.
- Accepted December 12, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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