Anti-allodynic effect of 2-(aminomethyl)adamantane-1-carboxylic acid in a rat model of neuropathic pain: A mechanism dependent on CaV2.2 channel inhibition |
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| Institution: | 1. Faculty of Pharmacy, Department of Pharmaceutical Chemistry, University of Athens, Panepistimioupoli-Zografou, GR-15771 Athens, Greece;2. School of Medicine FES Iztacala, National Autonomous University of Mexico (UNAM), Tlalnepantla, Mexico;3. Departmento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav), Sede Sur., México, D.F., Mexico;4. Department of Cell Biology, Cinvestav, Mexico City, Mexico;1. Istituto di Biochimica delle Proteine – CNR, Via P. Castellino 111, 80131 Napoli, Italy;2. Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy;3. Department of Chemistry, College of Science, King Saud University, PO Box 2455, Riyadh 11451, Saudi Arabia;4. Università degli Studi di Firenze, Polo Scientifico, Dipartimento NEIROFABA;Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy;1. Centre of Environmental Radioactivity CoE, Department of Environmental Sciences, Norwegian University of Life Sciences (NMBU), P. O. Box 5003, 1432, Ås, Norway;2. Centre of Environmental Radioactivity CoE, Norwegian Radiation Protection Authority (NRPA), P. O. Box 55, 1332, Østerås, Norway;1. N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow 119991, Russia;2. S.N. Winogradsky Institute of Microbiology, Russian Academy of Sciences, Moscow 117312, Russia;1. School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan;2. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC;3. Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC;4. Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC;5. Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC;6. Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan, ROC;7. Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC;8. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC;9. Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan, ROC |
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| Abstract: | Neuropathic pain is a serious physical disabling condition resulting from lesion or dysfunction of the peripheral sensory nervous system. Despite the fact that the mechanisms underlying neuropathic pain are poorly understood, the involvement of voltage-gated calcium (CaV) channels in its pathophysiology has justified the use of drugs that bind the CaV channel α2δ auxiliary subunit, such as gabapentin (GBP), to attain analgesic and anti-allodynic effects in models involving neuronal sensitization and nerve injury. GBP binding to α2δ inhibits nerve injury-induced trafficking of the α1 pore forming subunits of CaV channels, particularly of the N-type, from the cytoplasm to the plasma membrane of pre-synaptic terminals in dorsal root ganglion neurons and dorsal horn spinal neurons. In the search for alternative forms of treatment, in this study we describe the synthesis and pharmacological profile of a GABA derivative, 2-aminoadamantane-1-carboxylic acid (GZ4), which displays a close structure–activity relationship with GBP. Behavioral assessment using von Frey filament stimuli showed that GZ4 treatment reverted mechanical allodynia/hyperalgesia in an animal model of spinal nerve ligation-induced neuropathic pain. In addition, using the patch clamp technique we show that GZ4 treatment significantly decreased whole-cell currents through N-type CaV channels heterologously expressed in HEK-293 cells. Interestingly, the behavioral and electrophysiological time course of GZ4 actions reflects that its mechanism of action is similar but not identical to that of GBP. While GBP actions require at least 24 h and imply uptake of the drug, which suggests that the drug acts mainly intracellularly affecting channels trafficking to the plasma membrane, the faster time course (1–3 h) of GZ4 effects suggests also a direct inhibition of Ca2+ currents acting on cell surface channels. |
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| Keywords: | Allodynia Calcium channels Neuropathic pain Gabapentin |
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