Substance P‐induced respiratory excitation is blunted by δ‐receptor specific opioids in the rat medulla oblongata

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Abstract
The effects of substance P (SP) and the naturally occurring met‐enkephalin and the synthetic μ‐specific opioid agonist, DAGO (Tyr‐d‐Ala‐Gly‐N‐Methy‐Phe‐Gly‐ol) and the δ‐specific opioid agonist DADL (Tyr‐d‐Ala‐Gly‐Phe‐d‐Leu) on basal ventilation were investigated in halothane‐anaesthetized rats. Local injections of SP (0.75–1.5 nmol) in the ventrolateral medulla oblongata (VLM), e.g. nucleus paragigantocellularis, and nucleus reticularis lateralis increased ventilation because of an elevation of tidal volume. Met‐enkephalin induced a short‐lasting ventilatory depression mainly because of a depression of tidal volume. Activation of δ‐ and μ‐opioid receptors in the VLM by local application of DADL and DAGO, respectively, induced ventilatory depression, which was later in onset and more long‐lasting. Local administration of met‐enkephalin into the VLM also produced a long‐lasting inhibition of the SP‐induced ventilatory excitation. A similar blockade of the SP‐induced excitatory ventilatory response could be elicited by DADL but not by DAGO. This antagonistic effect was attenuated by local application of the δ‐opioid receptor antagonist ICI 154.129. We conclude that the naturally occurring met‐enkephalin as well as synthetic μ‐ and δ‐specific enkephalin analogues (DAGO and DADL, respectively) in VLM depress basal ventilation by an effect on inspiratory drive. There is a functional antagonism between activation of δ‐opioid receptors and SP receptors into the VLM in respect to respiratory regulation.

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