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Evaluation of Cebranopadol, a Dually Acting Nociceptin/Orphanin FQ And

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Evaluation of Cebranopadol, a Dually Acting Nociceptin/Orphanin FQ And Inflammopharmacol DOI 10.1007/s10787-017-0405-5 Inflammopharmacology ORIGINAL ARTICLE Evaluation of cebranopadol, a dually acting nociceptin/orphanin FQ and opioid receptor agonist in mouse models of acute, tonic, and chemotherapy-induced neuropathic pain 1 1 2 Kinga Sałat • Anna Furgała • Robert Sałat Received: 25 July 2017 / Accepted: 6 October 2017 Ó The Author(s) 2017. This article is an open access publication Abstract that of morphine. Used in combination and administered Background Cebranopadol (a.k.a. GRT-6005) is a dually simultaneously, 4 or 6 h after simvastatin, cebranopadol acting nociceptin/orphanin FQ and opioid receptor agonist did not potentiate antiallodynic activity of this cholesterol- that has been recently developed in Phase 2 clinical trials lowering drug. Cebranopadol did not induce any motor for painful diabetic neuropathy or cancer pain. It also deficits in the rotarod test. showed analgesic properties in various rat models of pain Conclusion Cebranopadol may have significant potential and had a better safety profile as compared to equi-anal- for the treatment of various pain types, including inflam- gesic doses of morphine. Since antinociceptive properties matory and chemotherapy-induced neuropathic pain. of cebranopadol have been studied mainly in rat models, in the present study, we assessed analgesic activity of sub- Keywords Cebranopadol Á Pain models Á cutaneous cebranopadol (10 mg/kg) in various mouse pain Neurogenic inflammation Á models. Chemotherapy-induced peripheral neuropathy Á Methods We used models of acute, tonic, and chronic pain Oxaliplatin Á Simvastatin induced by thermal and chemical stimuli, with a particular emphasis on pharmacoresistant chronic neuropathic pain evoked by oxaliplatin in which cebranopadol was used Introduction alone or in combination with simvastatin. Key results As shown in the hot plate test, the analgesic The International Association for the Study of Pain (IASP) activity of cebranopadol developed more slowly as com- defines pain as an unpleasant sensory and emotional pared to morphine (90–120 min vs. 60 min). Cebranopadol experience associated with actual or potential tissue dam- displayed a significant antinociceptive activity in acute age, or described in terms of such damage. The sensation of pain models, i.e., the hot plate, writhing, and capsaicin pain involves multiple signaling pathways, numerous tests. It attenuated nocifensive responses in both phases of neurotransmitters, and other mediators that are involved in the formalin test and reduced cold allodynia in oxaliplatin- the inhibitory or facilitatory control of pain intensity. These induced neuropathic pain model. Its efficacy was similar to 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 & Kinga Sałat receptor type involved and its location in the target tissue [email protected] (Argoff 2011). 1 In living organisms, endogenous opioids (endorphins, Chair of Pharmacodynamics, Department of enkephalins, and dynorphins) are key molecules in the Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St, 30-688 Krakow, Poland descending pain suppression pathways. Recently, it has been discovered that opioid receptors are widely dis- 2 Faculty of Production Engineering, Warsaw University of Life Sciences, 164 Nowoursynowska St, 02-787 Warsaw, tributed not only in the central but also peripheral nervous Poland system and in the non-neuronal tissues. There is also 123 K. Sałat et al. evidence from animal and human studies for the involve- inflammatory pain (CFA-induced arthritis model), bone ment of peripheral opioid receptors in analgesia, especially cancer pain model (Raffa et al. 2017), and neuropathic in the presence of inflammation (Sehgal et al. 2011), or pain: chronic constriction injury (CCI) and diabetic neu- neuropathy (Plein and Rittner 2017). ropathic pain models (Raffa et al. 2017) after intraplantar, The nociceptin/orphanin FQ opioid peptide receptor intracerebroventricular, intrathecal, intravenous (Tzschen- (NOP receptor) is the most recently discovered member of tke et al. 2017), subcutaneous, or oral route (Linz et al. the opioid receptor family. Together with its endogenous 2014). Compared to selective MOP receptor agonists, ce- ligand–nociceptin, also known as orphanin FQ (N/OFQ), it branopadol was more potent in models of chronic forms the fourth member of the opioid receptor family neuropathic than acute nociceptive pain and its duration of which is abundantly expressed in various body tissues. A action was long (Linz et al. 2014). Noteworthy, safety large body of evidence shows that the activation of pharmacology studies with cebranopadol demonstrated that N/OFQ-NOP system regulates functions of the central the development of analgesic tolerance in cebranopadol- nervous system being implicated in feeding, body weight treated animals subjected to CCI procedure was delayed as homeostasis, stress, stress-related psychiatric disorders— compared to equi-analgesic doses of morphine (Sałat et al. depression, anxiety, drug, and alcohol dependence (Witkin 2015a), and at analgesic doses, cebranopadol did not cause et al. 2014). Data from preclinical studies are also in line respiratory depression in a rat whole-body plethysmogra- with these findings showing that N/OFQ plays an important phy model, or motor coordination deficits in the rat rotarod role in comorbid neuropathic pain and post-traumatic stress test (Linz et al. 2014, 2017; Lambert et al. 2015;Gu¨nther disorder (Zhang et al. 2015), acute and chronic restraint et al. 2017). stress responses (Delaney et al. 2012), depression (Vitale The data presented above come from rat studies and et al. 2017), and other stress-related conditions (Leggett there is limited knowledge about antinociceptive properties et al. 2006; Witkin et al. 2014). of cebranopadol in mice. Moreover, these previous studies Apart from this, the N/OFQ-NOP pathway is also investigated the influence of cebranopadol on tactile allo- involved in the modulation of inflammatory and immune dynia but not thermal (i.e., heat or cold) allodynia and responses of the body by influencing migration of leuco- hyperalgesia. Hence, in the present study, we utilized cytes, cytokine secretion, and lymphocyte proliferation. mouse models of acute, tonic, and chronic pain induced by Recent findings showing the involvement of N/OFQ in thermal or chemical (inflammatory) stimuli, with a partic- inflammatory responses (Gavioli and Roma˜o 2011) and the ular emphasis on pharmacoresistant chronic neuropathic evidence for a role of NOP receptors and N/OFQ in the pain evoked by oxaliplatin. Oxaliplatin is a third-genera- modulation of neurogenic inflammation, migraine (Tajti tion platinum-based anti-tumor drug used to treat advanced et al. 2015), and airway tone (Singh et al. 2016) led to the colorectal cancer. Compared to other platinum-based hypothesis that N/OFQ-NOP system might be an important drugs, it has lower incidence of hematological adverse drug target for analgesic drugs. This is in part supported by effects and gastrointestinal toxicity, but in approximately the previous findings showing that the blockade of NOP 95% of patients, oxaliplatin causes severe neuropathic pain receptors can attenuate inflammation (Gavioli et al. 2015). episodes and increased sensitivity to cold (Manji 2013) On the other hand, this issue is not completely clear and which often lead to dose reduction or even treatment dis- unequivocally explored as there is also evidence for anal- continuation. These neuropathic pain episodes can be gesic efficacy of NOP agonists in neuropathic and effectively attenuated by l opioid peptide (MOP) and NOP inflammatory pain, both in animal models (Sukhtankar receptor agonists (Micheli et al. 2015). et al. 2013) and clinical trials (Sałat et al. 2015a). In the present study, we investigated the effect of Cebranopadol (a.k.a. GRT-6005; trans-60-fluoro-40,90- cebranopadol on cold nociceptive threshold of oxaliplatin- dihydro-N,N-dimethyl-4-phenyl-spiro[cyclohexane- treated mice. We used two protocols of its administration: 1,10(30H)-pyrano[3,4-b]indol]-4-amine) is a dually acting the first one which utilized this drug alone, and the second nociceptin/orphanin FQ and opioid receptor agonist (Ki one in which cebranopadol was used in combination with (nM)/EC50 (nM)/relative efficacy (%): human NOP simvastatin. Available data show potential effectiveness of receptor 0.9/13.0/89; human mu-opioid peptide (MOP) simvastatin in several animal models of pain (Shi et al. receptor 0.7/1.2/104; human kappa-opioid peptide (KOP) 2011; Miranda et al. 2011; Chen et al. 2013; Mansouri receptor 2.6/17/67; human delta-opioid peptide (DOP) et al. 2017), including inflammatory (Chen et al. 2013) and receptor 18/110/105) (Linz et al. 2014) that has been neuropathic pain models (Shi et al. 2011). First, in the recently developed in Phase 2 clinical trials for painful previous studies (Bhalla et al. 2015), simvastatin effec- diabetic neuropathy or cancer pain (reviewed in Sałat et al. tively reversed vincristine-induced neuropathic pain by 2015a). It showed analgesic properties in various rat anti-inflammatory effects and it was able to attenuate models of acute thermal pain, i.e., tail-flick model, chronic vincristine-induced increase in myeloperoxidase activity. 123 Evaluation of cebranopadol, a dually acting nociceptin/orphanin FQ and opioid receptor… Second, anti-inflammatory and anti-oxidant
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