A Study of the Role of Cyclic Adenosine 3′,5′‐monophosphate in the Depression by Opiates and Opioid Peptides of Excitatory Junction Potentials in the Mouse Vas Deferens

Abstract

I Excitatory junction potentials (ej.ps) were recorded with intracellular microelectrodes from smooth muscle cells of the mouse isolated vas deferens. The amplitude of the ej.p. was used as a measure of transmitter release evoked by applying single pulse stimuli to the intramural nerves. 2 Cyclic adenosine 3',5'-monophosphate (cyclic AMP) and dibutyryl cyclic AMP (db cyclic AMP, up to I mM) depressed the amplitude of ej.ps, probably by interacting with extracellular sites on the nerve terminals, similar to those responsive to adenosine.3 The phosphodiesterase inhibitors, 1-methyl-3-isobutyl xanthine (IBMX) and l-ethyl-4-hydrazino-1H-pyrazolo(3,4-b)pyridine-5-carboxylic acid, ethylester, hydrochloride (SQ20,006) increased ej.p. amplitude; this increase was much greater when the phosphodiesterase inhibitor was applied together with db cyclic AMP. 4 Neither the cyclic nucleotides nor the phosphodiesterase inhibitors altered the resting membrane potential of smooth muscle cells.5 The amplitude of the e.j.p. was depressed by normorphine, D-Ala2-Met5-enkephalinamide (DAEA) and D-Ala2-D-Leu5-enkephalin (DADL) with respective EC50s of 560 nM, 49 nm and 510 pM. 6 There was no change in the EC50 for normorphine in the presence of cyclic AMP (1 mM) or in the presence of a combination of IBMX (50 gM) and db cyclic AMP (500 gM). Similarly, the depression of the ej.p. by DAEA or DADL was not affected by the combination IBMX (500 gM) and db cyclic AMP (250 gM).7 These findings provide evidence against the hypothesis that a reduction in cyclic AMP levels in nerve terminals is an essential step in the inhibition by opiates and opioid peptides of transmitter release.

Cellular and Synaptic Adaptations Mediating Opioid Dependence

“…In various peripheral preparations from different species, the activation of all three receptor subtypes has been found to cause inhibition of transmitter release (264,318,507). The activation of potassium conductance and/or the inhibition of calcium conductance and not the inhibition of adenylyl cyclase have been argued to account for this action (35,355,415), although recent work suggests that under some conditions the inhibition of adenylyl cyclase can also account for some of the decrease in transmitter release (see sect. III B).…”

Low concentration of morphine protects against cell death, oxidative stress and calcium accumulation by nicotine in PC12 cells

“…Anot h er effect of morphine as an opioid is the regulation of ion channels in the cell membrane. It is obvious that all three opioid receptors are Ca 2+ -dependent (49).…”