ADX71943 and ADX71441, novel positive allosteric modulators of the GABA B receptor with distinct central/peripheral profiles, show efficacy in the monosodium iodoacetate model of chronic osteoarthritis pain in the rat
| Autor: | Sonia Poli, James D. Pomonis, Francoise Girard, Manfred Schneider, Mikhail Kalinichev, Cheryl L. Marker, Tansy Donovan-Rodriguez, Isabelle Royer-Urios, Hasnaà Haddouk, Simon T. Bate |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pharmacology business.industry Chronic pain Osteoarthritis GABAB receptor medicine.disease Rotarod performance test 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Anesthesia Threshold of pain Neuropathic pain Hyperalgesia Celecoxib medicine medicine.symptom business 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | European Journal of Pharmacology. 795:43-49 |
| ISSN: | 0014-2999 |
| Popis: | We tested novel positive allosteric modulators (PAMs) of the γ-aminobutyric acid receptor B (GABAB), ADX71943 and ADX71441in the monosodium iodoacetate model of chronic osteoarthritis pain in rats with the objective to delineate the role of peripheral versus central GABAB receptor populations in modulation of chronic pain. Anesthetized Sprague-Dawley rats received an injection of monosodium iodoacetate into the knee and were tested for hyperalgesia starting post-MIA day 14. Effects of compounds on ipsilateral joint compression threshold were evaluated on post-MIA day 14 (after acute treatment), as well as after repeated, daily treatment on days 21 and 28 (ADX71943 only) and were compared to those of celecoxib (30mg/kg, p.o.). The PAMs were also tested in the rat rotarod test for potential muscle-relaxant effects. Acutely, ADX71943 (1-30mg/kg, p.o.), the peripherally restricted PAM, resulted in similar increases in pain threshold across the doses on day 14, while showing reduced efficacy on day 21 and no efficacy on day 28. A clear reduction in the efficacy of celecoxib across testing was also noted in this experiment. Acutely ADX71441 (0.3-15mg/kg, p.o.), the central-peripheral PAM, resulted in over 2-fold increases in pain threshold at 15mg/kg (but not at lower doses) on day 14, while causing more modest effects on day 21. Celecoxib increased pain threshold after both acute and daily treatment, showing overall similar efficacy. Thus, early, presumably more inflammatory phase of osteoarthritis pain in more sensitive to GABAB PAMs with peripherally restricted profile, while later, presumably more neuropathic phase is more sensitive to PAMs with central-peripheral profile. |
| Databáze: | OpenAIRE |
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