Isobolographic analysis of the opioid-opioid interactions in a tonic and a phasic mouse model of induced nociceptive pain.

Hugo F Miranda,Juan Carlos Prieto-Rayo,Viviana Noriega,Pilar Zanetta,Juan Carlos Prieto,Nicolás Aranda,Fernando Sierralta

doi:10.1186/s12929-014-0062-6

Abstract

BackgroundOpioids have been used for the management of pain and coadministration of two opioids may induce synergism. In a model of tonic pain, the acetic acid writhing test and in a phasic model, the hot plate, the antinociceptive interaction between fentanyl, methadone, morphine, and tramadol was evaluated.ResultsThe potency of opioids in the writhing test compared to the hot plate assay was from 2.5 (fentanyl) to 15.5 (morphine) times, respectively. The ED50 was used in a fixed ratio for each of the six pairs of opioid combinations, which, resulted in a synergistic antinociception except for methadone/tramadol and fentanyl/tramadol which were additive, in the hot plate. The opioid antagonists naltrexone, naltrindole and nor-binaltorphimine, suggests that the synergism of morphine combinations are due to the activation of MOR subtypes with partially contribution of DOR and KOR, however fentanyl and methadone combinations are partially due to the activation of MOR and DOR subtypes and KOR lack of participation. The antinociceptive effects of tramadol combinations, are partially due to the activation of MOR, DOR and KOR opioid subtypes.ConclusionThese results suggets that effectiveness and magnitude of the interactions between opioids are dependent on pain stimulus intensity.

Highlights

Opioids have been used for the management of pain and coadministration of two opioids may induce synergism
After the administration of fentanyl (0.001, 0.003, 0.01 and 0.03 mg/kg) the ED50resulted in 0.016 ± 0.002 mg/kg
The results obtained in this work, demonstrate that the different opioids used in this work – fentanyl the most potent and tramadol the least potent – produced antinociceptive activity in the acetic acid writhing test and in the hot plate assay

Summary

Introduction

Opioids have been used for the management of pain and coadministration of two opioids may induce synergism. In a model of tonic pain, the acetic acid writhing test and in a phasic model, the hot plate, the antinociceptive interaction between fentanyl, methadone, morphine, and tramadol was evaluated. Previous studies have shown that majority of opioid effects, including analgesia, tolerance, and addiction, are primarily mediated by MORs, the effects of the other two opioid receptors remain elusive [1,2]. The acetic acid is an easy and fast screening model to access the activity of analgesic drugs and their mechanisms. These models induce a characteristic and quantifiable overt pain-like behaviour described as a writhing response or abdominal contortion [13]. The latency to pain reflex behaviour is measured

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