Concurrent nimodipine attenuates the withdrawal signs and the increase of cerebral dihydropyridine binding after chronic morphine treatment in rats

Abstract

The effect of chronic administration of dihydropyridine calcium channel antagonist nimodipine (1 mg/kg/day) given concurrently with morphine on the signs of morphine withdrawal and on the [3H]nitrendipine binding in the rat brain has been investigated. Chronic morphine administration in increasing daily doses from 20 mg/kg to 70 mg/kg for 24 days and consequent withdrawal for 24 h induced loss of body weight, wet dog shakes, episodes of writhing and yawning behaviour. The density of [3H]nitrendipine binding was elevated in the cortex and limbic structures but not in the striatum after chronic morphine treatment. Chronic concurrent administration of nimodipine prevented the loss of body weight and reduced the scores of wet dog shakes and writhing, but did not affect yawning behaviour at 24 h after morphine withdrawal. The concurrent nimodipine treatment also prevented the rise in the density of central dihydropyridine binding sites which occurred upon chronic morphine treatment. These results suggest that chronic nimodipine treatment attenuates the development of the withdrawal signs which occur upon the termination of chronic morphine treatment by preventing the up-regulation of the central dihydropyridine-sensitive binding sites.

Voltage‐Gated Ion Channels: 6.3 Calcium Channels

“…In rats an increased DHP binding induced by prolonged opioid treatment was localized to the cortex, hippocampus and brainstem but not to the cerebellum and striatum (Ramkumar and El-Fakahany, 1988). These data were confirmed by Zharkovsky et al (1993), who reported that in rats concurrent nimodipine treatment prevented the rise in the density of central DHP binding sites which occurred during chronic treatment. The authors suggest that chronic nimodipine treatment attenuates the development of withdrawal symptoms which occur on termination of chronic morphine treatment by preventing the upregulation of central DHP-sensitive binding sites.…”

Neurophamacology of Yawning

“…ACTH and physostigmine) [22,89] suggests that μ-opioid receptors in other brain regions may also be involved in the tonic inhibition of yawning. In addition, it is interesting to note that increases in yawning have been used for the identification and characterization of morphine withdrawal in humans and laboratory animals dating back to the 1930s [91][92][93].…”

Autoradiographic mapping of µ-opioid receptors during opiate tolerance and supersensitivity in the rat central nervous system

“…Ca 2+ antagonists increase the acute analgesic effects of opioids in humans (von Bormann et al 1985) and in rodents (Hoffmeister and Tettenborn 1986;Dierssen et al 1990;Díaz et al 1995a), whereas Ca 2+ channel activators, such as Bay K 8644, antagonised opioid antinociception (Dierssen et al 1990). Furthermore, Ca 2+ channel blockers have been shown to reduce the expression of opioid tolerance in humans (Santillán et al 1994(Santillán et al , 1998 and in rats (Dierssen et al 1990;Díaz et al 1995a;Michaluk et al 1998), and attenuate the withdrawal syndrome that is seen after chronic opioid administration (Bongianni et al 1986;Baeyens et al 1987; Barrios and Baeyens 1988;Pellegrini-Giampietro et al 1988;Alfaro et al 1990;Antkiewicz-Michaluk et al 1990, 1993Colado et al 1993;Zharkovsky et al 1993Zharkovsky et al , 1999Michaluk et al 1998).…”