ADX71943 and ADX71441, novel positive allosteric modulators of the GABAB receptor with distinct central/peripheral profiles, show efficacy in the monosodium iodoacetate model of chronic osteoarthritis pain in the rat

Eur J Pharmacol. 2017 Jan 15:795:43-49. doi: 10.1016/j.ejphar.2016.11.056. Epub 2016 Dec 1.

Abstract

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.

Keywords: ADX71441; ADX71943; Allosteric modulation; Chronic pain; GABA; GABA(B); Inflammatory pain; Neuropathic pain; Osteoarthritis.

MeSH terms

  • Acetamides
  • Allosteric Regulation / drug effects
  • Animals
  • Bacterial Proteins / pharmacology*
  • Bacterial Proteins / therapeutic use
  • Chronic Pain / chemically induced
  • Chronic Pain / complications*
  • Chronic Pain / drug therapy*
  • Chronic Pain / metabolism
  • Dose-Response Relationship, Drug
  • Hyperalgesia / complications
  • Hyperalgesia / drug therapy
  • Iodoacetates / pharmacology*
  • Male
  • Osteoarthritis / complications*
  • Pain Threshold / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-B / metabolism*
  • Rotarod Performance Test
  • Transcription Factors / pharmacology*
  • Transcription Factors / therapeutic use
  • Triazines

Substances

  • ADX71441
  • ADX71943
  • Acetamides
  • Bacterial Proteins
  • Iodoacetates
  • Receptors, GABA-B
  • Transcription Factors
  • Triazines