Chimeric compound – PK20 despite its therapeutic activity on nociceptive and inflammatory processes may affect respiration and blood pressure. Our objective was to evaluate influence of the hybrid composed of endomorphin-2 and neurotensin fragments on ventilation, heart rate and blood pressure in anesthetized and awake rats.
Intravenous administration of PK20 in the neurally intact rats evoked a dose-dependent apnoea followed by a transient insignificant increase in tidal volume and breathing rate. The blood pressure changes were biphasic: transient increase was replaced by prolonged hypotension. Midcervical vagotomy abrogated all post-PK20 respiratory effects. Hypotension was eliminated after blockade of neurotensin NTS 1 receptor, while respiratory changes were reduced by blockade of both: NTS 1 and μ opioid receptors. After PK20 intraperitoneal injection awake rats did not show any significant changes in ventilation and blood pressure.
This chimeric peptide should be used with care via intravenous administration in anesthetized animals since PK20 may evoke respiratory apnoea and hypotension. Nevertheless, applied intraperitoneally in the same dose in conscious rats induced no adverse effects.
Persevering attempts are carried out to create new therapeutic compounds devoid of adverse effects. PK20, a chimeric peptide characterized by having in its structure an opioid and neurotensin pharmacophores has been demonstrated to induce neuroprotective activity in ex vivo study (Kleczkowska et al., 2015), antinflammatory in in vivo studies (Kaczyńska et al., 2016) and dose-dependent prolonged, analgesic response in animal acute pain model (Kleczkowska et al., 2010). Importantly, the pain-relieving effect was stronger than a golden standard - morphine. It is well known that opioids with their large potency in pain alleviation have certain undesirable effects like tolerance, dependence and respiratory depression (Borgland, 2001, Contet et al., 2004, Kaczyńska and Szereda-Przestaszewska, 2005, Macintyre et al., 2011, Potter and Moon, 2015). Therefore in the present study we would like to investigate whether PK20 exerts any unfavourable cardiovascular and/or respiratory action in experimental animals.
The structure of PK20 has been described in details elsewhere (Kleczkowska et al., 2010). Briefly, neurotensin fragment has been modified by the presence of additional amino acids in order to gain a better enzymatic stability. The modification was performed in the C-terminal fragment (the most biologically active fragment of neurotensin, i.e. NT(8–13)), where Arg 8 and Arg 9 were replaced by lysine residues, substitutions that are known to leave potency unchanged. Supplementary substitution of Ile 12 by Tle (tert-leucine) optimized metabolic stability of PK20. The endomorphin-2 with the sequence of Tyr-Pro-Phe-Phe-NH 2 has been used as the second parent opioid element (N-terminal fragment of the whole PK20 molecule). To improve its enzymatic stability and receptor affinity the N-terminal Tyr 1 has been substituted by 2,6, dimethyl-tyrosine (Dmt) and Pro 2 has been replaced by D-lysine (Kleczkowska et al., 2013). Surprisingly, such modifications resulted in great activities towards receptors of interest as PK20 showed a very strong stimulation in both opioid and NTS 1 binding assays, with Emax values equal to 149.1% and 141.3% respectively (data not published).
In main part of present research we examined the cardiovascular and respiratory effects produced by an intravenous injection of PK20 in anesthetized rats. The contribution of vagal afferents and neurotensin and opioid receptors in the hybrid-induced cardiovascular and respiratory responses was tested, as well. In additional experiments, we checked whether intraperitoneal administration (i.p.) of PK20 in awake rats causes any respiratory and blood pressure responses.
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Animal procedures described in this paper were approved by the Local Ethical Committee in Warsaw (Poland) and performed in accordance with the European Community Council Directive of 24 November 1986 (86/609/EEC).
Table 1 shows the maximal response to an intravenous injection of different doses of PK20 on tidal volume (V T), mean arterial blood pressure (MAP) and duration and frequency of the apnoea. The lowest effective dose of 10 μg/kg to decrease the MAP initiated neither an apnoea nor significant alterations in V T. PK20 at 100 μg/kg had no effect on V T but in 33% of animals provoked an apnoea of mean duration 2.9±0.1 s. Two highest doses of PK20, 1 mg/kg and 2 mg/kg, induced an apnoea of mean duration
In this study we showed that a chimeric peptide PK20 injected intravenously in anesthetized rats dose-dependently exerted arrest of breathing, followed by transient tidal volume and respiratory rate fluctuations. Apart from respiratory effects immediate and short-lived pressor response replaced by extended hypotension was a constant occurrence.
Ile 9]PK20, analogous compound of PK20, cardiorespiratory action of which we tested in our previous research (Kaczyńska et al., 2014), caused modest
The study was supported by a grant from National Science Centre, Poland, No. 2014/13/B/NZ7/02247 .
Bupropion and naltrexone treatment for smoking cessation reduced nicotine withdrawal [806]. Oral naltrexone was not efficacious in reducing drinking or smoking for heavy-drinking smokers seeking smoking cessation treatment [526]. Opiates have been intimately implicated in sexual, reproductive, gestational and developmental processes as well as exerting strong endocrinological effects.
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