Respiratory and Cardiovascular Activity of LENART01, an Analgesic Dermorphin-Ranatensin Hybrid Peptide, in Anesthetized Rats

Abstract

Opioids are among the most effective drugs for treating moderate to severe pain. Unfortunately, opioid use, even short-term, can lead to addiction, tolerance, overdose, and respiratory depression. Therefore, efforts to design and develop novel compounds that would retain analgesic activity while reducing side effects continue unabated. The present study was designed to investigate the respiratory and cardiovascular effects of the hybrid peptide LENART01, which has evidenced potent antinociceptive and antimicrobial activity. This hybrid peptide, composed of N-terminally located dermorphin and C-terminal modified ranatensin pharmacophore, was tested in vivo in anesthetized rats. The main effect of LENART01 was apnea in 70% of examined animals, sighing, and a significant increase in blood pressure. Interestingly, the hybrid induced sighs less frequently than ranatensin, and apnea dependent on vagus nerve mu opioid receptor activation much less frequently and less intensely than dermorphin itself. This shows that LENART01 is a safer opioid system-related agent as compared to dermorphin for its prospective use in the treatment of pain.

Keywords: apnea; cardiovascular effects; dermorphin; ranatensin; respiratory effects.

Figure 1

Percentage change in respiratory variables after LENART01 and ranatensin injection. The effect of LENART01 after blockade of MOR, BB1/BB2, and D2R and after cervical vagotomy. Baseline—pre-administration value, minimal (MIN) and maximal (MAX) percent changes in V_T, F, and V_E within 2 min following drug injection. Box-plot format with median, Q1, Q3, min, max, and mean (x) values. * p < 0.05, ** p < 0.01 vs. the baseline value; #, o—p < 0.05; ##, oo—p < 0.01; #—vs. LENART01 group, o—vs. ranatensin group.

Figure 2

The number and the volume of sighs observed in the first 2 min following LENART01 and ranatensin challenge. The effect of LENART01 after blockade of MOR, BB1/BB2, and D2R and after cervical vagotomy. Note the increased volume and number of sighs after ranatensin injection, the lower number and even volume of sighs detected in the LENART01-treated animal groups, the increased number and volume of sighs after blockade of opioid receptors, and the lack of sighs after midcervical vagotomy. *, #—p < 0.05; **, ##—p < 0.01; ***, ###—p < 0.001; *—vs. LENART01; #—vs. ranatensin.

Figure 3

Percentage change in mean arterial blood pressure (MAP) and heart rate (HR) after LENART01 and ranatensin injection. The effect of LENART01 after blockade of MOR, BB1/BB2, and D2R and after cervical vagotomy. Baseline—pre-administration value, minimal (MIN) and maximal (MAX) percent changes in MAP and HR within 2 min following drug injection. Box-plot chart with median, Q1, Q3, min, max, and mean (x) value. #, o—p < 0.05; ##, oo—p < 0.01; ###, ooo—p < 0.001; # indicates the difference vs. the LENART01 group, and o indicates the difference vs. the ranatensin group, *—p < 0.05; **—p < 0.01 vs. baseline value.

Figure 4

Representative recordings depicting tidal volume (V_T), airflow (Vͦ), blood pressure (BP), and integrated electromyogram of the diaphragm (ꭍDia) in response to LENART01 (A), ranatensin (B), and dermophin (C) challenges. V.

Figure 5

The amino acid sequence of LENART01 with the corresponding pharmacophores indicated.