Neuropharmacology and analgesiaThe combination of opioid and neurotensin receptor agonists improves their analgesic/adverse effect ratio
Introduction
Nowadays, opioids remain the most prescribed analgesics to treat moderate to severe pain (Gomes et al., 2014, Munzing, 2017). Morphine, the prototypical opioid, mediates its actions mainly through the Mu opioid receptor (MOP). In addition to analgesia, morphine also produces a number of unwanted and debilitating effects such as drowsiness, constipation, nausea, respiratory depression, and tolerance (Benyamin et al., 2008). Analgesic tolerance to morphine develops such that the dose needed to maintain a given level of analgesia has to be constantly increased. In order to limit the development of analgesic tolerance and concomitant unwanted effects, drug combination represents a promising alternative to currently used opioids. Indeed, combining an opioid with another analgesic drug might reduce the unwanted effects normally associated to each individual drug. This was indeed found to be true when morphine was intrathecally injected with dexmedetomidine, a selective α2-adrenergic receptor agonist in a rat model of neuropathic pain (Kabalak et al., 2013). Similarly, the combined use of morphine and monoamine reuptake inhibitors was found to potentiate their respective analgesic effects in the rat formalin model (Shen et al., 2013).
We and others have shown that neurotensin (NT) can produce significant pain relief in various animal models of acute and chronic pain (Boules et al., 2006, Demeule et al., 2014, Fanelli et al., 2015, Fantegrossi et al., 2005, Guillemette et al., 2012, Roussy et al., 2008, Tétreault et al., 2013). First identified for its hypotensive effects, NT is also know to participate in a wide variety of physiological functions, including modulation of body temperature, myocardial performance, gastrointestinal tract motility and secretion (Osadchii, 2015, Zhao and Pothoulakis, 2006). According to its wide distribution throughout the central nervous system (Sarret and Beaudet, 2002), NT was also shown to exert brain functions, such as antipsychotic- and psychostimulant-like effects as well as regulation of food intake (Dobner, 2005, Dobner et al., 2003, Mazella et al., 2012). The physiological effects of NT are mediated by the activation of two closely related G protein-coupled receptors (GPCRs), namely NTS1 and NTS2 (Vincent et al., 1999). Importantly, NT-mediated analgesia was found to be independent of the opioid system. There is indeed compelling evidence demonstrating that opioid antagonists do not suppress NT-induced antinociception (Behbehani and Pert, 1984, Clineschmidt et al., 1982, Osbahr et al., 1981). Furthermore, NT also appears to be more potent than morphine in various pain tests (Nemeroff et al., 1979, al-Rodhan et al., 1991).
In the present study, we hypothesized that combining opioid and NT peptides will present some advantages over pure opioid-based therapies. We thus undertook to determine whether systemically administered morphine combined to An2-NT(8-13), consisting of the brain-penetrant peptide Angiopep-2 (An2) conjugated to NT(8-13) (Demeule et al., 2014), can exert additive or synergistic antinociceptive interaction. We therefore evaluated the analgesic effects of combining morphine and An2-NT(8-13) in the rat model of formalin-induced persistent pain, and determined the extent of drug interaction using isobolograms. We further determined whether this drug combination can reduce opioid-induced constipation or NT-induced drop in blood pressure, thus leading to a better analgesic benefit/adverse effect ratio.
Section snippets
Animals
Adult male Sprague-Dawley rats (225–250 g; Charles River Laboratories, St-Constant, QC, Canada) were maintained in a 12-h light/dark cycle and had ad libitum access to lab chow and water. Rats were acclimatized for 3 days to experimental room, manipulations and devices prior to the behavioral studies. All experiments were performed in a quiet room, different than the housing area, between 8:00 a.m. and 2:00 p.m. by the same experimenter. All experiments were approved by the animal care
Antinociceptive effect of morphine and An2-NT(8-13) in the rat formalin test
We first determined the analgesic potencies of morphine and An2-NT(8-13) following separate administration. Our results demonstrate that the administration of morphine (0.3–10 mg/kg, s.c.) induced a dose-dependent antinociceptive effect in the rat formalin test (Fig. 1A). The most important effect of morphine was observed during the inflammatory phase (21–60 min). Indeed, at 3 mg/kg and 10 mg/kg, morphine completely inhibited the formalin-induced nociceptive behaviors during the inflammatory
Discussion
Despite its negative impact on the patient's health outcomes, chronic pain remains a highly prevalent, debilitating and costly medical condition that is frequently undertreated or inadequately managed. Indeed, the pharmacotherapy of chronic pain, which mainly depends on the use of opioids still shows limited analgesic efficacy and dose-limiting adverse effects in clinical practice (Bruneau et al., 2018). Although the recent research efforts have significantly improved our understanding of pain
Acknowledgements
This work was supported by the Canadian Institute of Health Research (CIHR) (Grant nos. MOP-123399 and MOP-136871) awarded to L.G. and (Grant no. FDN-148413) awarded to PS. L.G. is the recipient of a Senior Salary support from the Fonds de la Recherche Québec – Santé. PS holds a Canada Research Chair in Neurophysiopharmacology of Chronic Pain. E.E. was the recipient of a PhD fellowship from the Institut de pharmacologie de Sherbrooke. E.E., P.S. and L.G. designed the study. E.E. and J.C.
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2020, European Journal of PharmacologyCitation Excerpt :This increasing attention is probably driven in part by the fact that NT drugs act as effective opioid-free medications for pain management, producing significant pain relief in various animal models of acute and chronic pain, including neuropathic pain for which opioids have shown their limitations (Guillemette et al., 2012; Perez de Vega et al., 2018; Tetreault et al., 2013). Importantly, the combination of NT analogs to opioids has also the potential to exert complementary (synergistic or additive) analgesic actions, thereby minimizing the adverse effects related to chronic opioid use (Boules et al., 2009, 2011; Eiselt et al., 2019). In recent years, changes in the pharmaceutical industry have led to renewed interest in the use of peptides as therapeutics (Fosgerau and Hoffmann, 2015; Kaspar and Reichert, 2013).
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2020, NeuropharmacologyCitation Excerpt :As described here, neurotensinergic signaling is involved in a number of different reward-related behaviors and plays a variety of contextually- and regionally-dependent roles. There has been interest in manipulating this system in the pursuit of novel treatments for schizophrenia (Kinkead and Nemeroff, 2006; Meltzer et al., 2004; Vadnie et al., 2016), pain (Dobner, 2006; Eiselt et al., 2019), and substance use disorders (Felszeghy et al., 2007; Ferraro et al., 2016). In the treatment of schizophrenia, agonism of the NTS system may serve as an antipsychotic on its own (Vadnie et al., 2016), or may serve to ameliorate the effects of a chronic antipsychotic regimen (Servonnet et al., 2017).
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2019, International Journal of SurgeryCitation Excerpt :Morphine, a mu-opioid receptor agonist, relieves pain by binding and activating the receptors in both the central and peripheral nervous systems [24]. As the most widely used narcotic for postoperative pain control, morphine has been reported a high incidence of adverse effects such as nausea, vomiting, headache, and urine retention, which could severely impede the postoperative convalescence [25,26]. Besides, drug dependence is also a major concern.