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Volume 16, Number 19, Issue of October 1, 1996 pp. 6046-6055
Copyright ©1996 Society for Neuroscience

Peptidergic Modulation of Synaptic Transmission in the Parabrachial Nucleus In Vitro: Importance of Degradative Enzymes in Regulating Synaptic Efficacy

Received April 3, 1996; revised June 14, 1996; accepted July 18, 1996.

Tarek M. Saleh¹, Samuel B. Kombian¹, Jeffrey A. Zidichouski^{1, 2}, and Quentin J. Pittman¹

¹ Neuroscience Research Group, University of Calgary, and ² Ciba-Geigy Canada Limited, Calgary, Alberta, Canada T2N 4N1

This study examined the effects of substance P (SP) and calcitonin gene-related peptide (CGRP) on synaptic transmission in a pontine slice containing the parabrachial nucleus (PBN). Stimulation of the ventral, external lateral portion of the PBN elicited glutamate-mediated EPSCs in cells recorded using the nystatin perforated-patch recording technique in the external lateral, external medial, and central lateral subnuclei of the PBN. Bath application of SP or CGRP dose-dependently and reversibly attenuated the evoked EPSC. The attenuation of the EPSC induced by both of these peptides was not accompanied by changes in input resistance of PBN cells over a wide voltage range, nor did these peptides alter the inward current induced by a brief bath application of AMPA. The combined application of subthreshold concentrations of these peptides revealed a synergistic interaction in reducing the evoked EPSC. The substance P neurokinin-1 receptor antagonist CGP49823 completely and reversibly blocked both the SP- and the CGRP-induced attenuation of the EPSC. However, the rat CGRP receptor antagonist human-CGRP_8-37 did not block the actions of CGRP or SP on the EPSC. Using a metabolically stable analog of SP, SP(5-11), or an endopeptidase inhibitor, phosphoramidon, we were able to demonstrate that CGRP enhances the SP effect by inhibiting an SP endopeptidase. Application of phosphoramidon also revealed an endogenous SP ``tone'' apparently made effective by blockade of the endopeptidase. These results suggest that SP (and CGRP indirectly through an inhibition of the SP endopeptidase) acts on presynaptic NK-1 receptors to cause an inhibition of excitatory transmission in the PBN. These results indicate an important role of endopeptidases in regulating synaptic modulation by peptides.

Key words: visceral afferent pathway; CGP49823; synergism; presynaptic modulation; nystatin-patch recording; endopeptidase; phosphoramidon; substance P; calcitonin gene-related peptide

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