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

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.

Keywords: NPFF receptors; apnea; endomorphin-1; neuropeptide FF; μ-opioid receptors.

Figure 1

Changes over time of (a) tidal volume (V_T); (b) frequency of breathing (F), (c) minute ventilation (V_E), (d) heart rate (HR) and (e) mean arterial blood pressure (MAP) after iv injection of various doses of NPFF. Significant drop in V_E is produced by the highest dose of NPFF. Short-lived increase in MAP is evoked mostly by the two highest doses of NPFF. The data are presented as median ± QD; * p < 0.05 vs. baseline value; n = 5–6 per dose.

Figure 2

The effect of iv injected NPFF on the number and duration of EM-1-induced apneas (a) and T_E test/T_E control ratio (b). The data has been shown as median ± QD (▲, thin whiskers) and mean ± SEM (−, bold whiskers); ○ episode of apnea or T_E test/T_E control ratio of a single rat. The number of apnea episodes are shown in-between slashes (a). Mann–Whitney test: # p < 0.05 vs. control (saline) group. Total number of tested animals per each NPFF dose: n = 5–7.

Figure 3

The dose dependent effect of icv NPFF administration on the number and duration of EM1-induced apneas (a) and T_E test/T_E control ratio (b). Note that NPFF at a dose of 20 μg eliminated EM-1 provoked apnea completely. The effect was blocked by NPFF receptor antagonist RF9. The data has been shown as median ± QD (▲, thin whiskers) and mean ± SEM (−, bold whiskers); ○ episode of apnea or T_E test/T_E control ratio of a single rat. The number of apnea episodes are shown in-between slashes (a). Mann–Whitney test: # p < 0.05 vs. control (saline) group. Total number of examined animals per each NPFF dose: n = 5–7.

Figure 4

Representative recordings of respiratory and blood pressure responses to intravenous EM-1 injection in: control rat injected icv with saline (a); pretreated with icv injection of 20 μg NPFF (b); and pretreated with icv injection of a mixture of 20 μg NPFF and 20 μg RF9 (an antagonist of NPFF receptors). The line above top traces shows the injection of EM-1. Appearance of apnea and a drop in arterial blood pressure after EM-1 injection (a); icv injection of NPFF abolished the presence of the apnea and hypotensive effect of EM-1 injection (b); coadministration of NPFF and RF9 restored the EM-1 ability to induce apnea and blood pressure decrease (c). V_T—tidal volume; V—airflow; BP—blood pressure; ʃDIA—integrated electromyogram of the diaphragm.