Preclinical Analgesic and Safety Evaluation of the GalR2-preferring Analog, NAX 810-2
| Autor: | Grzegorz Bulaj, Misty D. Smith, Cameron S. Metcalf, Daniel R. McDougle, Brian D. Klein, Liuyin Zhang |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine medicine.medical_treatment Analgesic Drug Evaluation Preclinical Pain Neuropeptide Galanin Stimulation Pharmacology Biochemistry Article Rats Sprague-Dawley Mice 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine medicine Animals ED50 Pain Measurement Analgesics Dose-Response Relationship Drug Chemistry General Medicine Rats Receptor Galanin Type 2 030104 developmental biology Nociception Anticonvulsant Anesthesia Sciatic nerve 030217 neurology & neurosurgery |
| Zdroj: | Neurochemical Research. 42:1983-1994 |
| ISSN: | 1573-6903 0364-3190 |
| DOI: | 10.1007/s11064-017-2229-5 |
| Popis: | The potential clinical utility of galanin peptidic analogs has been hindered by poor metabolic stability, lack of brain penetration, and hyperglycemia. In addition to possessing potent anticonvulsant efficacy, galanin analogs are analgesic in various assays. The purpose of these studies was to evaluate the lead galanin receptor type 2 (GalR2)-preferring analog, NAX 810-2, in various pain assays, as well as determine any potential for insulin inhibition, growth hormone stimulation, and cognitive impairment. NAX 810-2 was evaluated in mouse (carrageenan, formalin, tail flick, plantar incision) and rat pain models (partial sciatic nerve ligation). NAX 810-2 dose-dependently increased paw withdrawal latency following plantar administration of carrageenan (ED50 4.7 mg/kg). At a dose of 8 mg/kg, NAX 810-2 significantly attenuated nociceptive behaviors following plantar administration of formalin, and this was observed for both phase I (acute) and phase II (inflammatory) components of the formalin behavioral response. NAX-810-2 was active at higher doses in the mouse tail flick model (ED50 20.2 mg/kg) and similarly, reduced mechanical allodynia following plantar incision in mice at a dose of 24 mg/kg. NAX 810-2 also reduced mechanical allodynia in the partial sciatic nerve ligation model at a dose of 4 mg/kg. In addition, NAX 810-2 did not impair insulin secretion at doses of 2.5 and 8 mg/kg (acutely) or at a dose of 8 mg/kg given daily for 5 days. Similarly, 8 mg/kg (twice daily, 5 days) of NAX 810-2 did not increase growth hormone levels. These results demonstrate that NAX 810-2 possesses a favorable pre-clinical profile as a novel and first-in-class analgesic. |
| Databáze: | OpenAIRE |
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