Intracerebroventricular Neuropeptide FF Diminishes the Number of Apneas and Cardiovascular Effects Produced by Opioid Receptors’ Activation

Piotr Wojciechowski,Katarzyna Kaczyńska,Kryspin Andrzejewski

doi:10.3390/ijms21238931

Abstract

The opioid-induced analgesia is associated with a number of side effects such as addiction, tolerance and respiratory depression. The involvement of neuropeptide FF (NPFF) in modulation of pain perception, opioid-induced tolerance and dependence was well documented in contrast to respiratory depression. Therefore, the aim of the present study was to examine the potency of NPFF to block post-opioid respiratory depression, one of the main adverse effects of opioid therapy. Urethane-chloralose anaesthetized Wistar rats were injected either intravenously (iv) or intracerebroventricularly (icv) with various doses of NPFF prior to iv endomorphin-1 (EM-1) administration. Iv NPFF diminished the number of EM-1-induced apneas without affecting their length and without influence on the EM-1 induced blood pressure decline. Icv pretreatment with NPFF abolished the occurrence of post-EM-1 apneas and reduced also the maximal drop in blood pressure and heart rate. These effects were completely blocked by the NPFF receptor antagonist RF9, which was given as a mixture with NPFF before systemic EM-1 administration. In conclusion, our results showed that centrally administered neuropeptide FF is effective in preventing apnea evoked by stimulation of μ-opioid receptors and the effect was due to activation of central NPFF receptors. Our finding indicates a potential target for reversal of opioid-induced respiratory depression.

Highlights

The opioid-induced analgesia is associated with a number of side effects such as development of tolerance, addiction and respiratory depression
The doses tested were selected on the basis of a previous study that examined cardiovascular effects of intravenous neuropeptide FF (NPFF) [20]
Unlike other doses of NPFF the highest one used in the present experiments evoked a single episode of apnea lasting 3.7 s

Summary

Introduction

The opioid-induced analgesia is associated with a number of side effects such as development of tolerance, addiction and respiratory depression. The activity of opioids undergoes regulation by homeostatic antiopioid systems involving various neuropeptides: neuropeptide FF (NPFF), cholecystokinin (CCK), Tyr-MIF-1-related peptide, nociceptin/orphanin FQ and several others [1]. Neuropeptide FF (FLFQPQRFa) is a mammalian amidated neuropeptide originally isolated from bovine brain in 1985 and described as a pain modulating peptide with antiopioid activity on the morphine-induced analgesia in the rat [2]. A number of data indicates the involvement of NPFF system in cardiovascular regulation [15,16,17,18,19]. Intravenous administration of NPFF results in dose-dependent increase in blood pressure and heart rate [20,21,22], microinjected into the rat NTS, to the contrast, it evokes bradycardia [23]

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Results