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      Novel agonist of α 4β 2* neuronal nicotinic receptor with antinociceptive efficacy in rodent models of acute and chronic pain

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          Abstract

          Objective

          To demonstrate the antinociceptive and antihypersensitivity mechanisms of Cris-104 (1-{2-[5-(4-fluorophenyl)–1H-pyrazol-4-yl]ethyl}piperidine), a novel selective α 4β 2* nicotinic acetylcholine receptor (nAChR) agonist, in rodent acute/inflammatory and chronic pain models.

          Materials and methods

          Hot-plate and formalin tests in mice were used to examine Cris-104-induced antinociceptive effects on thermal/inflammatory pain. Cris-104 effects on hypersensitivity, norepinephrine (NE) release in the spinal dorsal horn, and neuronal activity in the locus coeruleus (LC) were examined in rats with lumbar spinal nerve ligation using behavioral, microdialysis, and extracellular recording methods. Cris-104 effects on spontaneous locomotion were examined in an open-field test.

          Results

          Cris-104 induced dose-dependent antinociception effects in hot-plate and formalin tests, and these effects were blocked by the general nAChR antagonist mecamylamine, the selective α 4β 2* nAChR antagonist dihydro-beta-erythroidine, and the α 2-adrenoceptor antagonist yohimbine, but not by the α 1-adrenoceptor antagonist prazosin. Systemic and spinally perfused Cris-104 increased NE concentrations in microdialysates from the spinal cord in both normal and SNL rats. Systemic Cris-104 increased neuronal activity in the LC of normal rats. Mecamylamine blocked the effects of Cris-104 on spinal NE release and LC neuronal activity. Systemic Cris-104 did not affect locomotor activity significantly.

          Conclusion

          The α 4β 2 neuronal nAChR agonist, Cris-104, was effective for treatment of pain via descending noradrenergic inhibition of pain signaling.

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          Most cited references 30

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          A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia.

          A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
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            An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat.

            We attempted to develop an experimental animal model for peripheral neuropathic pain. Under sodium pentobarbital anesthesia, both the L5 and L6 spinal nerves (group 1) or the L5 spinal nerve alone (group 2) of one side of the rat were tightly ligated. For comparison, a parallel study was conducted with another group of rats (group 3) which received a partial tight sciatic nerve ligation, a paradigm developed previously as a neuropathy model. Withdrawal latencies to application of radiant heat to the foot were tested for the next 16 weeks in all 3 groups. Sensitivity of the hind paw to mechanical stimulation was tested with von Frey filaments. The general behavior of each rat was noted during the entire test period. Results suggested that the surgical procedure in all 3 groups produced a long-lasting hyperalgesia to noxious heat (at least 5 weeks) and mechanical allodynia (at least 10 weeks) of the affected foot. In addition, there were behavioral signs of the presence of spontaneous pain in the affected foot. Therefore, we believe we have developed an experimental animal model for peripheral neuropathy using tight ligations of spinal nerves. The model manifests the symptoms of human patients with causalgia and is compatible with a previously developed neuropathy model. The present model has two unique features. First, the surgical procedure is stereotyped. Second, the levels of injured and intact spinal segments are completely separated, allowing independent experimental manipulations of the injured and intact spinal segments in future experiments to answer questions regarding mechanisms underlying causalgia.
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              Neuronal Nicotinic Acetylcholine Receptor Structure and Function and Response to Nicotine.

               John Dani (2015)
              Nicotinic acetylcholine receptors (nAChRs) belong to the "Cys-loop" superfamily of ligand-gated ion channels that includes GABAA, glycine, and serotonin (5-HT3) receptors. There are 16 homologous mammalian nAChR subunits encoded by a multigene family. These subunits combine to form many different nAChR subtypes with various expression patterns, diverse functional properties, and differing pharmacological characteristics. Because cholinergic innervation is pervasive and nAChR expression is extremely broad, practically every area of the brain is impinged upon by nicotinic mechanisms. This review briefly examines the structural and functional properties of the receptor/channel complex itself. The review also summarizes activation and desensitization of nAChRs by the low nicotine concentrations obtained from tobacco. Knowledge of the three-dimensional structure and the structural characteristics of channel gating has reached an advanced stage. Likewise, the basic functional properties of the channel also are reasonably well understood. It is these receptor/channel properties that underlie the participation of nAChRs in nearly every anatomical region of the mammalian brain.
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                Author and article information

                Journal
                J Pain Res
                J Pain Res
                Journal of Pain Research
                Journal of Pain Research
                Dove Medical Press
                1178-7090
                2018
                30 October 2018
                : 11
                : 2453-2462
                Affiliations
                [1 ]Program of Research in Drug Development of Biomedical Science, Institute of Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, rtakashisudo@ 123456gmail.com
                [2 ]Post-Graduation Program in Medicine (General Surgery) of Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, rtakashisudo@ 123456gmail.com
                [3 ]Department of Neurophysiology, Akita University School of Medicine, Akita, Japan
                [4 ]Cristalia Produtos Quimicos e Farmacêuticos Ltda, Itapira, São Paulo, Brazil
                Author notes
                Correspondence: Roberto T Sudo, Universidade Federal do Rio de Janeiro, Centro de Ciências da Saúde, Instituto de Ciências Biomédicas, Bloco J, Sala 14, Rio de Janeiro 21941-902, Brasil, Tel/Fax: +55 213 938 6505, Email rtakashisudo@ 123456gmail.com
                Article
                jpr-11-2453
                10.2147/JPR.S169637
                6214310
                30464575
                © 2018 Sudo et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Anesthesiology & Pain management

                epibatidine, cris-104, nicotinic receptor, pain

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