Effect of chronic morphine treatment on transmitter release from sympathetic varicosities of the mouse vas deferens

Abstract

1 Transmitter release from sympathetic varicosities of mouse vasa deferentia removed from animals which were chronically treated with morphine for 7 to 9 days has been evaluated.2 In control preparations increasing the extracellular calcium concentration ([Ca2"].) from 1 to 2 mM increased transmitter release by 3 fold while increasing [Ca2"]0 from 6 to 8 mM increased transmitter release by about 0.9 fold. Introduction of morphine (1.0 uM) produced a uniform decrease in transmitter release, shifting the relationship between transmitter release and [Ca2"]. to the right.3 Only sympathetic varicosities with probabilities of transmitter release greater than 0.01 were chosen for this study. In these varicosities the decrease in transmitter release induced by morphine in control preparations (bathed in [Ca2+]0 2.0 mM) was not observed following 7 to 9 days of morphine treatment. When the morphine was acutely withdrawn from these preparations transmitter release was more than 6 times the average level of transmitter release from control preparations. 4 The morphine induced increase in facilitation of transmitter release while stimulating with short trains of nerve impulses was not observed when the preparations were removed from animals which had been exposed to morphine for 7 to 9 days. When these preparations were acutely withdrawn from morphine there was a further decrease in the level of facilitation and a significant increase in depression of transmitter release when compared to control. 5The morphine induced decrease in probability of transmitter release when naive sympathetic varicosities in vitro were bathed with morphine (1 pM) was not observed following chronic morphine treatment of the animals for 7 to 9 days. When the morphine was acutely withdrawn from chronically morphine treated preparations the underlying increase in probabilities of transmitter release of sympathetic varicosities was unmasked.

Effect of morphine on the nerve terminal impulse and transmitter release from sympathetic varicosities innervating the mouse vas deferens

“…At the neuromuscular junction of amphibia the 4th power relationship between quantal release and [Ca2+JO, however, has been shown not to hold in very low or very high calcium concentrations (see Jenkinson, 1957;Dodge & Rahamimoff, 1967) and may depend on the initial probability of transmitter release. Lavidis, 1995c).…”

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

“…Although the present study has demonstrated an apparent decrease in the efficacy of both morphine and clonidine to inhibit transmitter release from sympathetic varicosities during CMT, the primary cause of this effect was shown to be a significant increase in transmitter release from sympathetic varicosities. This increase in transmitter release is not only produced by an increase in probability of transmitter release from sympathetic varicosities (as has been reported previously, Lavidis 1995a , 1995b ) but as was shown in the present study by an increase in the density of innervation. In the next study we aim to investigate the possible role of neurotrophins in the changes observed in the present study.…”

“…Although the enhancement of transmitter release from sympathetic varicosities undergoing withdrawal from CMT is mainly produced by an increase in the probability of transmitter release ( Lavidis, 1995b ), an increase in the density of sympathetic varicosities may also contribute to this enhancement. In the present investigation, we have observed a significant increase (31%) in the density of sympathetic varicosities of CMT vasa deferentia.…”

“…Further support for a common point of interaction between opioid receptors and α 2 ‐adrenoceptors has come from the CMT experiments. Acute withdrawal from CMT increases the probability of transmitter release from known numbers of sympathetic varicosities of the mouse vas deferens, possibly by enhancing calcium entry during nerve stimulation ( Lavidis, 1995b ), or by changing the phosphorylation state of vesicular associated proteins ( Nah et al ., 1993 ). In the present study we have demonstrated that enhancement of transmitter release from sympathetic varicosities following the development of tolerance to morphine ( Einstein & Lavidis, 1984b ; Lavidis, 1995b ) underlies the decrease in effectiveness of morphine and clonidine.…”

“…Tolerance to the effects of morphine on transmitter release is observed following CMT. This adaptive change becomes evident when the morphine is acutely withdrawn and is observed as an increase in transmitter release ( Montel et al ., 1975 ; Brodie et al ., 1980 ; Einstein & Lavidis, 1984a , 1984b , Lavidis, 1995b ). Although clonidine has been used to alleviate some of the symptoms of opiate withdrawal, a simple explanation of the interaction between opioid‐receptors and α 2 ‐adrenoceptors which can account for all previous observations has not materialized.…”