Effect of chronic morphine treatment on α₂‐adrenoceptor mediated autoinhibition of transmitter release from sympathetic varicosities of the mouse vas deferens

Abstract

1 The eect of chronic morphine treatment (CMT) on sympathetic innervation of the mouse vas deferens and on a 2 -adrenoceptor mediated autoinhibition has been examined using intracellular recording of excitatory junction potentials (EJPs) and histochemistry. 2 In chronically saline treated (CST) preparations, morphine (1 mM) and the a 2 -adrenoceptor agonist (clonidine, 1 mM) decreased the mean amplitude of EJPs evoked with 0.03 Hz stimulation by 81+8% (n=16) and 92+6% (n=7) respectively. In CMT preparations, morphine (1 mM) and clonidine (1 mM) decreased mean EJP amplitude by 68+8% (n=7) and 79+8% (n=7) respectively. 3 When stimulating the sympathetic axons at 0.03 Hz, the mean EJP amplitude recorded from smooth muscles acutely withdrawn from CMT was four times greater than for CST smooth muscles (40.7+3.8 mV, n=7 compared with 9.9+0.3 mV, n=7). 4 Part of the increase in mean EJP amplitude following CMT was produced by a 31% increase in the density of sympathetic axons and varicosities innervating the smooth muscle. 5 Results from the present study indicate that the eectiveness of a 2 -adrenoceptor mediated autoinhibition is only slightly reduced in CMT preparations. Most of the cross tolerance which develops between morphine, clonidine and a 2 -adrenoceptor mediated autoinhibition occurs as a consequence of increased ecacy of neuromuscular transmission which is produced by an increase in the probability of transmitter release and an increase in the density of sympathetic innervation.

A pharmacological modulation of opiate withdrawal using an up-/down-regulation of the noradrenergic system in opiate-dependent rats

“…Paul and Tran, 1995) and as a consequence higher doses of clonidine are needed to be efficient in opiate-dependent patients during opiate detoxification procedures. This crosstolerance seems to occur partly as a consequence of increased efficacy of neuromuscular transmission which is produced by an increase in the probability of transmitter release and an increase in the density of sympathetic innervation (Karunanithi and Lavidis, 2001). Therefore, pre-treatment with yohimbine could potentiate clonidine efficiency via an up-/down-regulation which could through several mechanisms including an interference of neurotransmitter release but also through a re-sensibilization of adrenoreceptors.…”

Involvement of Ca2+-dependent PKCs in the adaptive changes of μ-opioid pathways to sympathetic denervation in the guinea pig colon

“…Functionally related  2 -adrenoceptor and opioid receptor pathways may be involved in adaptive changes occurring in excitable cells when a net stimulus is chronically changed. Tolerance and dependence to the effect of opiates may represent an example of adaptive sensitivity change leading to altered function not only of opioid but also of a variety of other neuronal systems, including  2 -adrenoceptors, in the central nervous system and peripherally [11,12]. Several reports have described the occurrence of changes in  2 -adrenoceptor sensitivity after chronic morphine treatment in the enteric nervous system (ENS) [13][14][15], which represents a complex and integrative neuronal network suitable for the study of neuronal plasticity [16].…”

“…From a molecular viewpoint, the functional interplay between opioid receptors and  2 -adrenoceptors has been suggested to depend upon several factors, including changes in transmitter release, alterations at the receptor level and in the intracellular signalling pathways coupled to receptor activation [12,18,19]. At this latter regard, a key role in the modulation of intracellular responses is played by protein kinase C (PKC).…”

Effect of chronic clonidine treatment on transmitter release from sympathetic varicosities of the guinea‐pig vas deferens

“…Chronic morphine treatment of mice results in the development of tolerance to both morphine (Montel et al ., 1975; Einstein & Lavidis, 1984b; Lavidis, 1995a) and clonidine (Solomon & Gebhart, 1988; Stevens et al ., 1988; Karunanithi & Lavidis, 2001). Tolerance to both morphine and clonidine in sympathetic nerves develops through a counter‐adaptive process, resulting in a substantial increase in the probability of transmitter release from varicosities (Montel et al ., 1975; Einstein & Lavidis, 1984a; Karunanithi & Lavidis, 2001). In the present study we have investigated whether chronic clonidine treatment (CCT), by acting on different pre‐synaptic receptors, evokes similar counter‐adaptations as seen in chronically morphine treated preparations.…”