Abstract
BackgroundCebranopadol (a.k.a. GRT-6005) is a dually acting nociceptin/orphanin FQ and opioid receptor agonist that has been recently developed in Phase 2 clinical trials for painful diabetic neuropathy or cancer pain. It also showed analgesic properties in various rat models of pain and had a better safety profile as compared to equi-analgesic doses of morphine. Since antinociceptive properties of cebranopadol have been studied mainly in rat models, in the present study, we assessed analgesic activity of subcutaneous cebranopadol (10 mg/kg) in various mouse pain models.MethodsWe used models of acute, tonic, and chronic pain induced by thermal and chemical stimuli, with a particular emphasis on pharmacoresistant chronic neuropathic pain evoked by oxaliplatin in which cebranopadol was used alone or in combination with simvastatin.Key resultsAs shown in the hot plate test, the analgesic activity of cebranopadol developed more slowly as compared to morphine (90–120 min vs. 60 min). Cebranopadol displayed a significant antinociceptive activity in acute pain models, i.e., the hot plate, writhing, and capsaicin tests. It attenuated nocifensive responses in both phases of the formalin test and reduced cold allodynia in oxaliplatin-induced neuropathic pain model. Its efficacy was similar to that of morphine. Used in combination and administered simultaneously, 4 or 6 h after simvastatin, cebranopadol did not potentiate antiallodynic activity of this cholesterol-lowering drug. Cebranopadol did not induce any motor deficits in the rotarod test.ConclusionCebranopadol may have significant potential for the treatment of various pain types, including inflammatory and chemotherapy-induced neuropathic pain.
Highlights
The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage
GRT-6005) is a dually acting nociceptin/orphanin FQ and opioid receptor agonist that has been recently developed in Phase 2 clinical trials for painful diabetic neuropathy or cancer pain
The paws of mice are very sensitive to heat at temperatures that are not harmful to the skin. The characteristic responses such as jumping, licking of the paws are of central origin and it is thought that drugs with antinociceptive properties in the hot plate test act primarily in the spinal medulla and/or higher central nervous system levels (Vogel and Vogel 1997)
Summary
The International Association for the Study of Pain (IASP) defines pain as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. The sensation of pain involves multiple signaling pathways, numerous neurotransmitters, and other mediators that are involved in the inhibitory or facilitatory control of pain intensity These mechanisms affect the perception of stimuli as non-painful or painful, respectively, but their positive or negative modulation of pain signaling is strongly dependent on the receptor type involved and its location in the target tissue (Argoff 2011). Cebranopadol (a.k.a. GRT-6005) is a dually acting nociceptin/orphanin FQ and opioid receptor agonist that has been recently developed in Phase 2 clinical trials for painful diabetic neuropathy or cancer pain. GRT-6005) is a dually acting nociceptin/orphanin FQ and opioid receptor agonist that has been recently developed in Phase 2 clinical trials for painful diabetic neuropathy or cancer pain It showed analgesic properties in various rat models of pain and had a better safety profile as compared to equi-analgesic doses of morphine. Since antinociceptive properties of cebranopadol have been studied mainly in rat models, in the present study, we assessed analgesic activity of subcutaneous cebranopadol (10 mg/kg) in various mouse pain models
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