Short communicationIntraventricular insulin reduces the antinociceptive effect of [d-Ala2, NMePhe4, Gly-ol5]enkephalin in mice
Introduction
It has been reported that the antinociceptive potency of morphine is decreased in spontaneously diabetic (C57BL/KsJ-db/db) mice, an animal model of non-insulin-dependent diabetes mellitus (type II diabetes) (Simon and Dewey, 1981). In this regard, we recently reported that (±)-5-[4-(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl-methoxy)benzyl]-2,4-thiazolidinedione (CS-045), an oral antidiabetic agent, dramatically improved the antinociceptive effect of morphine in C57BL/KsJ-db/db mice (Kamei et al., 1997). In contrast to the hyperglycemia and hypoinsulinemia observed in streptozotocin-induced diabetic mice, spontaneously diabetic mice (C57BL/KsJ-db/db) are hyperglycemic and hyperinsulinemic (Coleman and Hummel, 1967). CS-045 decreases plasma glucose and insulin levels in spontaneously diabetic mice (Fujiwara et al., 1988, Fujiwara et al., 1991). Therefore, it seems likely that not only hyperglycemia but also hyperinsulinemia may be responsible for the reduction in the antinociceptive effects of μ-opioid receptor agonists in C57BL/KsJ-db/db mice. However, there is no information available regarding the effect of insulin on the antinociceptive effects of μ-opioid receptor agonists.
Thus, the first aim of the present study was to investigate the effect of i.c.v. insulin on the antinociceptive effect of [d-Ala2, NMePhe4, Gly-ol5]enkephalin (DAMGO) to clarify the hypothesis that hyperinsulinemia may be responsible for the reduction in the antinociceptive effects of μ-opioid receptor agonists. We also examined the effect of lavendustin A, a specific inhibitor of tyrosine kinase (O'Dell et al., 1991, Onoda et al., 1989), on the antinociceptive effect of DAMGO in C57BL/KsJ-db/db mice, because insulin has been reported to activate phosphorylation of the receptor protein tyrosine kinase.
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Animals
Male C57BL/KsJ diabetic (db/db) mice and C57BL/KsJ non-diabetic (db/++) mice were generously supplied by Dr. Fujiwara (Institute of Experimental Animals, Tokyo University, School of Medicine, Tokyo, Japan) and maintained at Yokohama City University, School of Medicine. C57BL/KsJ-db/db mice were used for the experiments at 20–24 weeks of age. Male 6-week-old ICR mice weighing about 25 g were purchased from Tokyo Animal Laboratory, Tokyo, Japan. They had free access to food and water in an animal
Effects of insulin on the antinociceptive effect of DAMGO
Intracerebroventricular administration of DAMGO (5.6 ng) produced an average %MPE of 63.4±9.3% in mice. As shown in Fig. 1A, pretreatment with insulin (1 and 3 mU, i.c.v.) 60 min prior to i.c.v. challenge with DAMGO dose dependently attenuated the antinociceptive effect of DAMGO (5.6 ng). Furthermore, pretreatment with insulin (3 mU, i.c.v.) produced a 2.1-fold rightward shift in the dose-response curve for DAMGO-induced antinociception (Fig. 1B).
The effects of lavendustin A on the
Discussion
The results of this study demonstrate that i.c.v. pretreatment with insulin (3 mU) attenuated the inhibition of the tail-flick response induced by i.c.v. DAMGO in mice. Furthermore, this attenuation of i.c.v. DAMGO-induced antinociception by insulin was reversed by i.c.v. pretreatment with lavendustin A. Onoda et al. (1989)and O'Dell et al. (1991)demonstrated that the inhibitory effects of lavendustin A on serine and threonine kinase, such as protein kinase C, protein kinase A and Ca2+
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