Evaluation of cebranopadol, a dually acting nociceptin/orphanin FQ and opioid receptor agonist in mouse models of acute, tonic, and chemotherapy-induced neuropathic pain

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.

Are Opioids Effective in Relieving Neuropathic Pain?

“…In animal models, cebranopadol administered through peripheral, spinal, and supraspinal routes exerted potent and efficacious antihyperalgesic, antiallodynic, and antinociceptive effects, therefore being useful in NP [215,216]. Additionally, animal studies have portrayed a better safety profile of cebranopadol compared to equianalgesic doses of morphine [217]. In a phase II randomized, doubleblind, placebo-and active-controlled trial of cebranopadol in LBP patients, with and without NP component, cebranopadol was safe, and it displayed a good analgesic efficacy similar to tapentadol [218].…”

Searching for analgesic drug candidates alleviating oxaliplatin‐induced cold hypersensitivity in mice

“…For this purpose, researchers use different tests: acetone drop test (Ito, Kobuchi, Shimizu, & Katsuyama, ), cold water test (K. Sałat et al., ), and cold plate test (Sałat, Furgała, & Sałat, ); various temperatures the oxaliplatin‐treated animal is exposed to—ranging from −4°C (Hache et al., ) through 0°C (Pevida, Lastra, Hidalgo, Baamonde, & Menéndez, ), 2°C (Mika, Osikowicz, Makuch, & Przewlocka, ; Nakanishi et al., ), 4°C (Berrocoso et al., ; Hache et al., ; Masocha & Parvathy, ) to 5°C (Sambasevam et al., ; Zhao et al., ); different time points at which they assess animals’ nociceptive threshold—from 2 hr (Zhao et al., ) to 7 days after oxaliplatin injection (Hache et al., ; Zhao et al., ); and distinct behavioral measures taken as end‐points: paw withdrawal latencies (i.e., latencies to paw licking and paw shaking) (Pevida et al., ), only jumping behavior (Hache et al., ), or lifting behavior (Mika et al., ), escape behaviors graded with a score from no response to vigorous activity (i.e., jumping) (Zhao et al., ) or the duration of the nocifensive response (Nakanishi et al., ). In these experimental conditions, both rat (Ito et al., ) and mouse strains are used (reviewed in Marmiroli et al., ; Sałat et al., ). Importantly, the schedules of oxaliplatin administration also vary among laboratories (a single‐dose protocol (Hache et al., ; Sałat et al., ), a repeated dose protocol (Sakurai et al., )).…”

“…In these experimental conditions, both rat (Ito et al, 2018) and mouse strains are used (reviewed in Marmiroli et al, 2017;Sałat et al, 2018). Importantly, the schedules of oxaliplatin administration also vary among laboratories (a single-dose protocol (Hache et al, 2015;Sałat et al, 2018), a repeated dose protocol (Sakurai et al, 2009)). In light of the abovementioned methodological differences in measuring cold pain, one may encounter difficulties in the analysis and comparison of the results obtained for analgesic drugs used for the attenuation of oxaliplatin-induced neuropathic pain.…”

Biochemical, functional and pharmacological characterization of novel bifunctional peptide ligands and nociceptin variants

“…Among the NOP/MOP receptor agonists, the bifunctional ligand cebranopadol has been found to be effective even in the nanomolar range on the MOP, DOP, KOP and NOP receptors 149,150 . In in vivo tests, it has proved to be an effective substance 149,[151][152][153] .…”

“…In in vivo tests, it has proved to be an effective substance 149,[151][152][153] . This compound is currently in phase II and III clinical trials 150,152 investigating the efficacy, safety and tolerability of the orally administered drug. Trials on patients with moderate to severe osteoarthritis are currently in phase IIa 152 .…”