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Peripheral Administration of Selective Glycine Transporter-2 Inhibitor, Oleoyl-D-Lysine, Reverses Chronic Neuropathic Pain but Not Acute or Inflammatory Pain in Male Mice.
Wilson, Bruce S; Peiser-Oliver, Julian; Gillis, Alexander; Evans, Sally; Alamein, Claudia; Mostyn, Shannon N; Shimmon, Susan; Rawling, Tristan; Christie, MacDonald J; Vandenberg, Robert J; Mohammadi, Sarasa A.
Affiliation
  • Wilson BS; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (B.S.W., J.P.-O., A.G., S.E., C.A., S.N.M, M.J.C., R.J.V., S.A.M.) and School of Mathematical and Physical Sciences, University of Technology, Sydney, Australia (S.S., T.R.).
  • Peiser-Oliver J; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (B.S.W., J.P.-O., A.G., S.E., C.A., S.N.M, M.J.C., R.J.V., S.A.M.) and School of Mathematical and Physical Sciences, University of Technology, Sydney, Australia (S.S., T.R.).
  • Gillis A; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (B.S.W., J.P.-O., A.G., S.E., C.A., S.N.M, M.J.C., R.J.V., S.A.M.) and School of Mathematical and Physical Sciences, University of Technology, Sydney, Australia (S.S., T.R.).
  • Evans S; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (B.S.W., J.P.-O., A.G., S.E., C.A., S.N.M, M.J.C., R.J.V., S.A.M.) and School of Mathematical and Physical Sciences, University of Technology, Sydney, Australia (S.S., T.R.).
  • Alamein C; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (B.S.W., J.P.-O., A.G., S.E., C.A., S.N.M, M.J.C., R.J.V., S.A.M.) and School of Mathematical and Physical Sciences, University of Technology, Sydney, Australia (S.S., T.R.).
  • Mostyn SN; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (B.S.W., J.P.-O., A.G., S.E., C.A., S.N.M, M.J.C., R.J.V., S.A.M.) and School of Mathematical and Physical Sciences, University of Technology, Sydney, Australia (S.S., T.R.).
  • Shimmon S; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (B.S.W., J.P.-O., A.G., S.E., C.A., S.N.M, M.J.C., R.J.V., S.A.M.) and School of Mathematical and Physical Sciences, University of Technology, Sydney, Australia (S.S., T.R.).
  • Rawling T; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (B.S.W., J.P.-O., A.G., S.E., C.A., S.N.M, M.J.C., R.J.V., S.A.M.) and School of Mathematical and Physical Sciences, University of Technology, Sydney, Australia (S.S., T.R.).
  • Christie MJ; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (B.S.W., J.P.-O., A.G., S.E., C.A., S.N.M, M.J.C., R.J.V., S.A.M.) and School of Mathematical and Physical Sciences, University of Technology, Sydney, Australia (S.S., T.R.).
  • Vandenberg RJ; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (B.S.W., J.P.-O., A.G., S.E., C.A., S.N.M, M.J.C., R.J.V., S.A.M.) and School of Mathematical and Physical Sciences, University of Technology, Sydney, Australia (S.S., T.R.).
  • Mohammadi SA; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia (B.S.W., J.P.-O., A.G., S.E., C.A., S.N.M, M.J.C., R.J.V., S.A.M.) and School of Mathematical and Physical Sciences, University of Technology, Sydney, Australia (S.S., T.R.) sarasa.mohammadi@sydney.edu.au.
J Pharmacol Exp Ther ; 382(3): 246-255, 2022 09.
Article in En | MEDLINE | ID: mdl-35779948
Aberrations in spinal glycinergic signaling are a feature of pain chronification. Normalizing these changes by inhibiting glycine transporter (GlyT)-2 is a promising treatment strategy. However, existing GlyT2 inhibitors (e.g., ORG25543) are limited by narrow therapeutic windows and severe dose-limiting side effects, such as convulsions, and are therefore poor candidates for clinical development. Here, intraperitoneally administered oleoyl-D-lysine, a lipid-based GlyT2 inhibitor, was characterized in mouse models of acute (hot plate), inflammatory (complete Freund's adjuvant), and chronic neuropathic (chronic constriction injury) pain. Side effects were also assessed on a numerical rating score, convulsions score, for motor incoordination (rotarod), and for respiratory depression (whole body plethysmography). Oleoyl-D-lysine produced near complete antiallodynia for chronic neuropathic pain, but no antiallodynia/analgesia in inflammatory or acute pain. No side effects were seen at the peak analgesic dose, 30 mg/kg. Mild side effects were observed at the highest dose, 100 mg/kg, on the numerical rating score, but no convulsions. These results contrasted markedly with ORG25543, which reached less than 50% reduction in allodynia score only at the lethal/near-lethal dose of 50 mg/kg. At this dose, ORG25543 caused maximal side effects on the numerical rating score and severe convulsions. Oleoyl-D-lysine (30 mg/kg) did not cause any respiratory depression, a problematic side effect of opiates. These results show the safe and effective reversal of neuropathic pain in mice by oleoyl-D-lysine and provide evidence for a distinct role of glycine in chronic pain over acute or short-term pain conditions. SIGNIFICANCE STATEMENT: Partially inhibiting glycine transporter (GlyT)-2 can alleviate chronic pain by restoring lost glycinergic function. Novel lipid-based GlyT2 inhibitor ol-D-lys is safe and effective in alleviating neuropathic pain, but not inflammatory or acute pain. Clinical application of GlyT2 inhibitors may be better suited to chronic neuropathic pain over other pain aetiologies.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Respiratory Insufficiency / Acute Pain / Chronic Pain / Neuralgia Type of study: Prognostic_studies Limits: Animals Language: En Journal: J Pharmacol Exp Ther Year: 2022 Document type: Article Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Respiratory Insufficiency / Acute Pain / Chronic Pain / Neuralgia Type of study: Prognostic_studies Limits: Animals Language: En Journal: J Pharmacol Exp Ther Year: 2022 Document type: Article Country of publication: United States