Anti-nociceptive effects of dual neuropeptide antagonist therapy in mouse model of neuropathic and inflammatory pain
1
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Background: Neurokinin-1 (NK1) and calcitonin gene-related peptide (CGRP) play a vital role in pain pathogenesis, and these proteins’ antagonists have attracted attention as promising pharmaceutical candidates. The authors investigated the antinociceptive effect of co-administration of the CGRP antagonist and an NK1 antagonist on pain models compared to conventional single regimens. Methods: C57Bl/6J mice underwent sciatic nerve ligation for the neuropathic pain model and were injected with 4% formalin into the hind paw for the inflammatory pain model. Each model was divided into four groups: vehicle, NK1 antagonist, CGRP antagonist, and combination treatment groups. The NK1 antagonist aprepitant (BIBN4096, 1 mg/kg) or the CGRP antagonist olcegepant (MK-0869, 10 mg/ kg) was injected intraperitoneally. Mechanical allodynia, thermal hypersensitivity, and anxiety-related behaviors were assessed using the von Frey, hot plate, and elevated plus-maze tests. The flinching and licking responses were also evaluated after formalin injection. Results: Co-administration of aprepitant and olcegepant more significantly alleviated pain behaviors than administration of single agents or vehicle, increasing the mechanical threshold and improving the response latency. Anxiety-related behaviors were also markedly improved after dual treatment compared with either naive mice or the neuropathic pain model in the dual treatment group. Flinching frequency and licking response after formalin injection decreased significantly in the dual treatment group. Isobolographic analysis showed a meaningful additive effect between the two compounds. Conclusions: A combination pharmacological therapy comprised of multiple neuropeptide antagonists could be a more effective therapeutic strategy for alleviating neuropathic or inflammatory pain.
Abstract
Background: Neurokinin-1 (NK1) and calcitonin gene-related peptide (CGRP) play a vital role in pain pathogenesis, and these proteins’ antagonists have attracted attention as promising pharmaceutical candidates. The authors investigated the antinociceptive effect of co-administration of the CGRP antagonist and an NK1 antagonist on pain models compared to conventional single regimens. Methods: C57Bl/6J mice underwent sciatic nerve ligation for the neuropathic pain model and were injected with 4% formalin into the hind paw for the inflammatory pain model. Each model was divided into four groups: vehicle, NK1 antagonist, CGRP antagonist, and combination treatment groups. The NK1 antagonist aprepitant (BIBN4096, 1 mg/kg) or the CGRP antagonist olcegepant (MK-0869, 10 mg/ kg) was injected intraperitoneally. Mechanical allodynia, thermal hypersensitivity, and anxiety-related behaviors were assessed using the von Frey, hot plate, and elevated plus-maze tests. The flinching and licking responses were also evaluated after formalin injection. Results: Co-administration of aprepitant and olcegepant more significantly alleviated pain behaviors than administration of single agents or vehicle, increasing the mechanical threshold and improving the response latency. Anxiety-related behaviors were also markedly improved after dual treatment compared with either naive mice or the neuropathic pain model in the dual treatment group. Flinching frequency and licking response after formalin injection decreased significantly in the dual treatment group. Isobolographic analysis showed a meaningful additive effect between the two compounds. Conclusions: A combination pharmacological therapy comprised of multiple neuropeptide antagonists could be a more effective therapeutic strategy for alleviating neuropathic or inflammatory pain.
참고문헌 (46)
- Schou WS, "Calcitonin gene-related peptide and pain : a systematic review", J Headache Pain, 18, pp.34~ (2017)
- van Hecke O, "Neuropathic pain in the general population : a systematic review of epidemiological studies", Pain, 155, pp.654~662 (2014)
- Cavalli E, "The neuropathic pain : an overview of the current treatment and future therapeutic approaches", Int J Immunopathol Pharmacol, 33, pp.2058738419838383~ (2019)
- Bouhassira D, "Patient perspective on herpes zoster and its complications : an observational prospective study in patients aged over 50 years in general practice", Pain, 153, pp.342~349 (2012)
- Iyengar S, "The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine", Pain, 158, pp.543~559 (2017)
- Hunyady Á, "Hemokinin-1 is an important mediator of pain in mouse models of neuropathic and inflammatory mechanisms", Brain Res Bull, 147, pp.165~173 (2019)
- Navratilova E, "Substance P and inflammatory pain : getting it wrong and right simultaneously", Neuron, 101, pp.353~355 (2019)
- Chen W, "Neurokinin 1 receptor activation in the rat spinal cord maintains latent sensitization, a model of inflammatory and neuropathic chronic pain", Neuropharmacology, 177, pp.108253~ (2020)
- Ramírez-García PD, "A pH-responsive nanoparticle targets the neurokinin 1 receptor in endosomes to prevent chronic pain", Nat Nanotechnol, 14, pp.1150~1159 (2019)
- Teodoro FC, "Peripheral substance P and neurokinin-1 receptors have a role in inflammatory and neuropathic orofacial pain models", Neuropeptides, 47, pp.199~206 (2013)
- Gautam M, "Role of neurokinin type 1 receptor in nociception at the periphery and the spinal level in the rat", Spinal Cord, 54, pp.172~182 (2016)
- Hirsch S, "The CGRP receptor antagonist BIBN4096BS peripherally alleviates inflammatory pain in rats", Pain, 154, pp.700~707 (2013)
- Christensen SL, "Targeting CGRP via receptor antagonism and antibody neutralisation in two distinct rodent models of migraine-like pain", Cephalalgia, 39, pp.1827~1837 (2019)
- Lee SE, "Involvement of substance P and calcitonin gene-related peptide in development and maintenance of neuropathic pain from spinal nerve injury model of rat", Neurosci Res, 58, pp.245~249 (2007)
- Baron R, "Neuropathic pain : diagnosis, pathophysiological mechanisms, and treatment", Lancet Neurol, 9, pp.807~819 (2010)
- Finnerup NB, "Neuropathic pain : from mechanisms to treatment", Physiol Rev, 101, pp.259~301 (2021)
- histogranin and morphine in rat models of pain, "Pharmacol Res Perspect", 2014, e00032~
- Michot B, "Differential effects of calcitonin gene-related peptide receptor blockade by olcegepant on mechanical allodynia induced by ligation of the infraorbital nerve vs the sciatic nerve in the rat", Pain, 153, pp.1939~1948 (2012)
- Betti C, "dual alleviation of acute and neuropathic pain by fused opioid agonist-neurokinin 1 antagonist peptidomimetics", ACS Med Chem Lett, 6, pp.1209~1214 (2015)
- Medeiros P, "An adapted chronic constriction injury of the sciatic nerve produces sensory, affective, and cognitive impairments : a peripheral mononeuropathy model for the study of comorbid neuropsychiatric disorders associated with neuropathic pain in rats", Pain Med, 22, pp.338~351 (2021)
- Mannangatti P, "Differential effects of aprepitant, a clinically used neurokinin-1 receptor antagonist on the expression of conditioned psychostimulant versus opioid reward", Psychopharmacology (Berl), 234, pp.695~705 (2017)
- Mulder IA, "Anti-migraine calcitonin gene-related peptide receptor antagonists worsen cerebral ischemic outcome in mice", Ann Neurol, 88, pp.771~784 (2020)
- 이일옥, "Effects of Different Concentrations of Formalin on Paw Edema and Pain Behaviors in Rats", Journal of Korean Medical Science, 17(1), pp.81~85 (2002), 대한의학회
- Greco R, "Effects of CGRP receptor antagonism in nitroglycerin-induced hyperalgesia", Cephalalgia, 34, pp.594~604 (2014)
- Zhuo M, "Neural mechanisms underlying anxiety-chronic pain interactions", Trends Neurosci, 39, pp.136~145 (2016)
- Walf AA, "The use of the elevated plus maze as an assay of anxiety-related behavior in rodents", Nat Protoc, 2, pp.322~328 (2007)
- Tallarida RJ, "Drug combinations : tests and analysis with isoboles", Curr Protoc Pharmacol, 72, pp.9.19.1~9.19.19 (2016)
- Keller M, "Lack of efficacy of the substance p(neurokinin1receptor)antagonist aprepitant in the treatment of major depressive disorder", Biol Psychiatry, 59, pp.216~223 (2006)
- Tebas P, "A randomized, placebo controlled, double masked phase IB study evaluating the safety and antiviral activity of aprepitant, a neurokinin-1 receptor antagonist in HIV-1 infected adults", PLoS One, 6, pp.e24180~ (2011)
- Voss T, "A phase IIb randomized, double-blind, placebocontrolled trial of ubrogepant for the acute treatment of migraine", Cephalalgia, 36, pp.887~898 (2016)
- Herbert MK, "Why are substance P(NK1)-receptor antagonists ineffective in pain treatment?", Anaesthesist, 51, pp.308~319 (2002)
- Hill R, "NK1(substance P)receptor antagonists--why are they not analgesic in humans", Trends Pharmacol Sci, 21, pp.244~246 (2000)
- Kroenke K, "Association between anxiety, health-related quality of life and functional impairment in primary care patients with chronic pain", Gen Hosp Psychiatry, 35, pp.359~365 (2013)
- De Gregorio D, "Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain", Pain, 160, pp.136~150 (2019)
- McWilliams LA, "Depression and anxiety associated with three pain conditions : results from a nationally representative sample", Pain, 111, pp.77~83 (2004)
- Roeska K, "Anxiety-like behaviour in rats with mononeuropathy is reduced by the analgesic drugs morphine and gabapentin", Pain, 139, pp.349~357 (2008)
- Wu Y, "Pain aversion and anxiety-like behavior occur at different times during the course of chronic inflammatory pain in rats", J Pain Res, 10, pp.2585~2593 (2017)
- Muñoz M, "Involvement of substance P and the NK-1 receptor in human pathology", Amino Acids, 46, pp.1727~1750 (2014)
- Zocchi A, "Effects of antidepressant drugs and GR 205171, an neurokinin-1(NK1)receptor antagonist, on the response in the forced swim test and on monoamine extracellular levels in the frontal cortex of the mouse", Neurosci Lett, 345, pp.73~76 (2003)
- Borbély É, "Hemokinin-1 mediates anxiolytic and anti-depressantlike actions in mice", Brain Behav Immun, 59, pp.219~232 (2017)
- Schorscher-Petcu A, "Role of central calcitonin gene-related peptide(CGRP)in locomotor and anxiety-and depression-like behaviors in two mouse strains exhibiting a CGRP-dependent difference in thermal pain sensitivity", J Mol Neurosci, 39, pp.125~136 (2009)
- Araya EI, "Contribution of intraganglionic CGRP to migraine-like responses in male and female rats", Cephalalgia, 40, pp.689~700 (2020)
- Puig S, "Formalin-evoked activity in identified primary afferent fibers : systemic lidocaine suppresses phase-2activity", Pain, 64, pp.345~355 (1996)
- 조수영, "Antinociceptive Effect of Intrathecal Nefopam and Interaction with Morphine in Formalin-Induced Pain of Rats", The Korean Journal of Pain, 26(1), pp.14~20 (2013), 대한통증학회
- Rivat C, "Non-nociceptive environmental stress induces hyperalgesia, not analgesia, in pain and opioid-experienced rats", Neuropsychopharmacology, 32, pp.2217~2228 (2007)