Effect of a Novel, Orally Active Matrix Metalloproteinase-2 and -9 Inhibitor in Spinal and Trigeminal Rat Models of Neuropathic Pain

• Published in: Journal of oral & facial pain and headache Vol. 29; no. 3; p. 286
• Main Authors: Henry, Michael A, Fairchild, Dara D, Patil, Mayur J, Hanania, Taleen, Hain, Heather S, Davis, Scott F, Malekiani, Sam A, Hu, Andrew, Sucholeiki, Roy, Nix, Darrell, Sucholeiki, Irving
• Format: Journal Article
• Language: English
• Published: United States 2015
• Subjects: Administration, Oral; Amines - therapeutic use; Animals; Cyclohexanecarboxylic Acids - therapeutic use; Disease Models, Animal; Gabapentin; gamma-Aminobutyric Acid - therapeutic use; Hyperalgesia - drug therapy; Indoles - therapeutic use; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors - therapeutic use; Neuralgia - drug therapy; Propionates - therapeutic use; Rats; Rats, Sprague-Dawley; Spinal Nerves; Thiophenes - therapeutic use; Trigeminal Nerve
• ISSN: 2333-0384; 2333-0376
• DOI: 10.11607/ofph.1350

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. 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. 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. 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.