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

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.

Magnesium Salt, a Simple Strategy to Improve Methadone Analgesia in Chronic Pain: An Isobolographic Preclinical Study in Neuropathic Mice

“…Besides, the antinociceptive effects showed by magnesium and copper ions also coincide with those obtained in other studies using formalininduced pain, where systemic magnesium improved the antinociceptive effect of ketamine (Vujovićet al, 2017) and copper-NSAIDs complexes exhibited higher antinociceptive effect than NSAIDs alone (Gumilar et al, 2012). The foregoing results also showed that the MgSO 4 /methadone and CuSO 4 / methadone combinations produced higher antinociception than methadone alone, an opiate agonist that has proven to be effective in thermal and mechanical pain models (Lemberg et al, 2006), as well as in chemonociception (Miranda et al, 2014) and different models of neuropathic pain (Erichsen et al, 2005). The main and most important result of the present study was that MgSO 4 and methadone interacted synergistically in the intraplantar formalin pain model, which means that there was a potentiation of the antinociceptive effect of the drugs when given in combination.…”

Effects of acepromazine-morphine and acepromazine-methadone premedication on the minimum alveolar concentration of isoflurane in dogs

“…In support of the present findings, an unpublished study from the authors' laboratory, employing the same experimental design as in the present study, indicated that IM administered morphine (0.5 mg kg À1 ) was associated with a decrease in ISO MAC of 18%. Thus, it appears that methadone results in a greater decrease in ISO MAC than does morphine at the doses studied, although the relative potency of these drugs must be taken into account when making comparisons, and methadone is reported to be more potent than morphine in rats and mice (Peckham & Traynor 2006;Miranda et al 2014).…”

“…Thus, it appears that methadone results in a greater decrease in ISO MAC than does morphine at the doses studied, although the relative potency of these drugs must be taken into account when making comparisons, and methadone is reported to be more potent than morphine in rats and mice (Peckham & Traynor ; Miranda et al. ).…”

Antinociceptive and Anti-inflammatory Effects of Combined Administration of a-Tocopherol and Morphine in Acetic Acid Induced Writhing Test

“…The opioid receptors are normally stimulated by endogenous peptides which are produced in response to noxious stimulation 8 . Different investigators of different countries have experimented that morphine has visceral anti nociceptive and anti inflammatory effect in acetic acid induced writhing test [9][10][11] . aT is a primary membrane bound, lipid soluble, chain breaking antioxidant 11 among the eight different types of vitamin E. Recently, the analgesic and anti-inflammatory effects of aT have been demonstrated in different experimental animals [12][13][14] .…”