Effect of a novel, orally active matrix metalloproteinase-2 and -9 inhibitor in spinal and trigeminal rat models of neuropathic pain

Michael A. Henry, Dara D. Fairchild, Mayur J. Patil, Taleen Hanania, Heather S. Hain, Scott F. Davis, Sam A. Malekiani, Andrew Hu, Roy Sucholeiki, Darrell Nix, Irving Sucholeiki

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9 Scopus citations

Abstract

Aims: To study the effects of a novel matrix metalloproteinase-2 (MMP-2) and MMP-9 inhibitor, AQU-118, on mechanical allodynia in the spinal nerve ligation (SNL) model of neuropathic pain and the chronic constriction injury of the infraorbital nerve (CCI-IoN) model of neuropathic orofacial pain. Methods: Five groups of SNL rats were given daily oral doses of AQU-118 (5, 10, 20 mg/kg), gabapentin (100 mg/kg), or vehicle (0.5% methylcellulose) and then paw withdrawal threshold was measured with von Frey filaments (VF). Three groups of CCI-IoN rats were given daily oral doses of either AQU-118 (40 mg/kg), gabapentin (100 mg/kg), or vehicle (0.5% methylcellulose) and then mechanical allodynia was measured with facial VF and non-reflex-based orofacial stimulation test (OFST) assay. Naïve rats were also tested for the effect of AQU-118 (40 mg/kg) on basal sensitivity to mechanical stimulation/locomotive activity. Results: Mechanical allodynia in SNL rats was attenuated by gabapentin (100 mg/kg) and AQU-118 (in a dose-dependent manner). Mechanical allodynia in CCI-IoN rats was also attenuated (in an equipotent manner) by both AQU-118 (40 mg/kg) and gabapentin (100 mg/kg) as measured by both facial VF and OFST assay. Upon cessation of either AQU-118 or gabapentin, VF-related responses in both models and OFST assay times reverted to levels observed in vehicle-treated rats. No statistically significant change was observed in locomotive activity/paw withdrawal threshold by AQU-118 (40 mg/kg) in naïve rats. Conclusion: The results demonstrated that oral AQU-118 attenuates mechanical allodynia in both neuropathic pain models and with efficacies that mirror gabapentin at the 40 mg/kg dose used in the CCI-IoN model but without effect on basal sensitivity to mechanical stimulation/locomotive activity. These findings support a possible role for MMP-2/-9 in the etiology of neuropathic pain and also suggest that inhibition strategies represent a viable treatment option.

Original languageEnglish (US)
Pages (from-to)286-296
Number of pages11
JournalJournal of Oral and Facial Pain and Headache
Volume29
Issue number3
DOIs
StatePublished - 2015

Keywords

  • Allodynia
  • Inhibitor
  • Matrix metalloproteinase
  • MMP-2
  • MMP-9
  • Operant
  • Orofacial pain

ASJC Scopus subject areas

  • Medicine(all)

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    Henry, M. A., Fairchild, D. D., Patil, M. J., Hanania, T., Hain, H. S., Davis, S. F., Malekiani, S. A., Hu, A., Sucholeiki, R., Nix, D., & Sucholeiki, I. (2015). Effect of a novel, orally active matrix metalloproteinase-2 and -9 inhibitor in spinal and trigeminal rat models of neuropathic pain. Journal of Oral and Facial Pain and Headache, 29(3), 286-296. https://doi.org/10.11607/ofph.1350