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Effect of chronic morphine treatment on alpha(2)-adrenoceptor mediated autoinhibition of transmitter release from sympathetic varicosities of the mouse vas deferens.

ABSTRACT: 1. The effect of chronic morphine treatment (CMT) on sympathetic innervation of the mouse vas deferens and on alpha(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 microM) and the alpha(2)-adrenoceptor agonist (clonidine, 1 microM) 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 microM) and clonidine (1 microM) 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 When stimulating the sympathetic axons at 0.03 Hz, the mean EJP amplitude recorded from smooth muscles acutely withdrawn from CMT was four times greater than for CST smooth muscles (40.7+/-3.8 mV, n=7 compared with 9.9+/-0.3 mV, n=7). 4.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 effectiveness of alpha(2)-adrenoceptor mediated autoinhibition is only slightly reduced in CMT preparations. Most of the cross tolerance which develops between morphine, clonidine and alpha(2)-adrenoceptor mediated autoinhibition occurs 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.

SUBMITTER: Karunanithi S

PROVIDER: S-EPMC1572583 | biostudies-other | 2001 Jan

REPOSITORIES: biostudies-other

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Project description:Prejunctional nicotinic acetylcholine receptors (nAChRs) amplify postganglionic sympathetic neurotransmission, and there are indications that intraterminal Ca(2+) stores might be involved. However, the mechanisms by which nAChR activation stimulates neurotransmitter release at such junctions is unknown. Rapid local delivery (picospritzing) of the nAChR agonist epibatidine was combined with intracellular sharp microelectrode recording to monitor spontaneous and field-stimulation-evoked neurotransmitter release from sympathetic nerve terminals in the mouse isolated vas deferens. Locally applied epibatidine (1 µM) produced 'epibatidine-induced depolarisations' (EIDs) that were similar in shape to spontaneous excitatory junction potentials (SEJPs) and were abolished by nonselective nAChR antagonists and the purinergic desensitizing agonist ?,?-methylene ATP. The amplitude distribution of EIDs was only slightly shifted towards lower amplitudes by the selective ?7 nAChR antagonists ?-bungarotoxin and methyllcaconitine, the voltage-gated Na(+) channel blocker tetrodotoxin or by blocking voltage-gated Ca(2+) channels with Cd(2+). Lowering the extracellular Ca(2+) concentration reduced the frequency of EIDs by 69%, but more surprisingly, the Ca(2+)-induced Ca(2+) release blocker ryanodine greatly decreased the amplitude (by 41%) and the frequency of EIDs by 36%. Ryanodine had no effect on electrically-evoked neurotransmitter release, paired-pulse facilitation, SEJP frequency, SEJP amplitude or SEJP amplitude distribution. These results show that activation of non-?7 nAChRs on sympathetic postganglionic nerve terminals induces high-amplitude junctional potentials that are argued to represent multipacketed neurotransmitter release synchronized by intraterminal Ca(2+)-induced Ca(2+) release, triggered by Ca(2+) influx directly through the nAChR. This nAChR-induced neurotransmitter release can be targeted pharmacologically without affecting spontaneous or electrically-evoked neurotransmitter release.

Project description:1. The effects of the main component of the Tityus serrulatus scorpion venom, toxin TsTX-I, were studied on the contractility and release of neurotransmitters in the rat vas deferens. Since TsTX-I is known to act on sodium channels, we used veratridine, another sodium channel agent, for comparison. 2. Toxin TsTX-I induced concentration-dependent contractions with an EC(50) value of 47.8+/-0.1 nM and a maximum effect of 84.4+/-10.4% of that for BaCl(2). 3. Contractions by TsTX-I were abolished by denervation or tetrodotoxin (0.1 microM), showing that the toxin effects depend on the integrity of sympathetic nerve terminals. 4. To check for the presence of a noradrenergic component, experiments were conducted after removal of adrenergic stores in nerve terminals by reserpinization (10 mg kg(-1), 24 h prior to experiments) or blockade of alpha(1) adrenoceptors by prazosin (30 microM), showing that these procedures did not modify the response to TsTX-I, and therefore that adrenoceptors were not involved in contractions. 5. To check for the presence of a purinergic component, experiments were carried out after blockade of P(2X) receptors by suramin (0.1 mM) or desensitization by alpha,beta-methylene-ATP (30 microM). These agents greatly abolished the contractile response to TsTX-I (about 83% by desensitization and 96% by suramin), showing the involvement of purinergic receptors. 6. The release of noradrenaline and purinergic agents (ATP, ADP, AMP and adenosine) was detected by HPLC. Together, the total release of purines in the presence of TsTX-I was about 42 times higher than in the control group. In contrast, TsTX-I did not modify the overflow of noradrenaline, showing that the release was selective for purines. 7. The release of purinergic agents was reduced by the N-type calcium channel blocker omega-conotoxin GVIA (1 microM) and by the P/Q-type blocker omega-conotoxin MVIIC (1 microM), showing that the effects of TsTX-I are calcium-dependent. 8. The results show that TsTX-I produced a selective release of purines from postganglionic sympathetic nerves in the rat vas deferens.

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Effect of chronic morphine treatment on alpha(2)-adrenoceptor mediated autoinhibition of transmitter release from sympathetic varicosities of the mouse vas deferens.

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