The behavioral effects of a mixed efficacy antinociceptive peptide, VRP26, following chronic administration in mice

Abstract

Rationale VRP26 displays mu opioid receptor agonist and delta opioid receptor antagonist activity in vitro, a pharmacological profile purported to produce reduced tolerance, dependence, and rewarding effects. We hypothesized that VRP26 would display reduced adverse effects after chronic administration as compared with the traditional opioid analgesic fentanyl. Objective To explore the development of tolerance, dependence and conditioned place preference of VRP26 as compared with the traditional opioid analgesic fentanyl. Methods The antinociceptive effects of VRP26 and fentanyl were assessed using the mouse warm water tail withdrawal (WWTW) assay. Measurement of antinociceptive tolerance and physical dependence occurred after seven days of continuous administration of either fentanyl (0.3 mg/kg/day) or VRP26 (10 mg/kg/day); tolerance was measured by a shift in the antinociceptive dose response curve in the WWTW assay. Physical dependence was determined by observation of withdrawal symptoms after precipitated withdrawal. Rewarding effects were measured by the ability of VRP26 or fentanyl to produce conditioned place preference. Results Fentanyl produced significant tolerance and dependence, as well as significant conditioned place preference. VRP26 produced neither tolerance nor physical dependence, nor did it produce significant conditioned place preference. Conclusions These results suggest that chronic treatment with VRP26 may produce less tolerance or physical dependence than chronic treatment with clinically available mu opioid analgesics such as fentanyl. Additionally, VRP26 produces less rewarding effects than fentanyl. This desirable in vivo profile may be due to the mixed efficacy nature of VRP26 and could provide the framework for safer opioid analgesics.

A Novel Mu-Delta Opioid Agonist Demonstrates Enhanced Efficacy With Reduced Tolerance and Dependence in Mouse Neuropathic Pain Models

“…Gp120 IIIb protein was obtained from SPEED BioSystems, LLC (#YCP1549, Gaithersburg, MD). 3 Hdiprenorphine (NET1121250UC) and 35 S-GTPγS (NEG030H250UC) were obtained from PerkinElmer (Waltham, MA). A βarrestin2-EGFP fusion protein DNA vector was a kind gift from Dr. Larry Barak at the Duke University Addiction Research GPCR Assay Bank.…”

“…4,5,19,20,38,39 These compounds produced anti-nociception in acute pain models with decreased tolerance and dependence, validating the approach. 3,5 Intriguingly however, dual MOR-DOR agonists have also been shown to be beneficial in a small number of studies. The dual agonist MMP-2200 produced anti-nociception with reduced tolerance, dependence, locomotor activation, and self-administration.…”

In vivo effects of μ‐opioid receptor agonist/δ‐opioid receptor antagonist peptidomimetics following acute and repeated administration

“…Opioids produce both their pain‐relieving and adverse effects through stimulation of the μ‐opioid receptor (μ‐receptor); therefore, creating more selective ligands for the μ‐receptor is unlikely to reduce the incidence of adverse events. There are reports that the co‐administration of μ‐receptor agonist with a δ‐receptor antagonist produces μ‐receptor‐mediated antinociception with reduced tolerance and dependence liabilities (Abdelhamid et al ., ; Fundytus et al ., ; Hepburn et al ., ; Purington et al ., ; Schiller, ; Anand et al ., ; Váradi et al ., ), and similar results have been found in δ‐receptor knockout (KO) animals (Zhu et al ., ). As a result, the development of μ‐receptor agonist/δ‐receptor antagonist compounds – mixed efficacy ligands – has been explored, and several peptide (Purington et al ., ; Purington et al ., ; Schiller et al ., ; Schmidt et al ., ; Anand et al ., ; Cai et al ., ), peptide‐like (Balboni et al ., ; Balboni et al ., ; Salvadori et al ., ; Lee et al ., ; Bender et al ., ; Mosberg et al ., ) and alkaloid (Anathan et al ., ; Anathan et al ., ; Horan et al ., ; Healy et al ., ) compounds have been described.…”

“…As a result, the development of μ‐receptor agonist/δ‐receptor antagonist compounds – mixed efficacy ligands – has been explored, and several peptide (Purington et al ., ; Purington et al ., ; Schiller et al ., ; Schmidt et al ., ; Anand et al ., ; Cai et al ., ), peptide‐like (Balboni et al ., ; Balboni et al ., ; Salvadori et al ., ; Lee et al ., ; Bender et al ., ; Mosberg et al ., ) and alkaloid (Anathan et al ., ; Anathan et al ., ; Horan et al ., ; Healy et al ., ) compounds have been described. Noteworthy ligands are the peptides DIPPψNH 2 (Schiller et al ., ) and VRP26 (Anand et al ., ), the bivalent ligand MDAN‐21 (Lenard et al ., ) and the multifunctional opioid alkaloid UMB425 (Healy et al ., ). All show some improvement over morphine, but both DIPPψNH 2 and UMB425 produce significant tolerance and dependence after chronic administration, and MDAN‐21 was effective in some (Aceto et al ., ; Daniels et al ., ), but not all (Aceto et al ., ), measures of antinociception.…”

“…All show some improvement over morphine, but both DIPPψNH 2 and UMB425 produce significant tolerance and dependence after chronic administration, and MDAN‐21 was effective in some (Aceto et al ., ; Daniels et al ., ), but not all (Aceto et al ., ), measures of antinociception. We previously reported that VRP26 produces no antinociceptive tolerance or physical dependence after 7 days of continuous administration and produces little conditioned place preference (CPP) (Anand et al ., ); however, VRP26 is difficult to synthesize and purify and therefore makes a poor drug candidate. While these μ‐receptor agonist/δ‐receptor antagonist compounds display promising effects in vivo , there is still room for improvement.…”