title: Effect of a Novel, Orally Active Matrix Metalloproteinase-2 and -9 Inhibitor in Spinal and Trigeminal Rat Models of Neuropathic Pain.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Henry
authors.forename: Dara D
authors.initials: DD
authors.lastname: Fairchild
authors.forename: Mayur J
authors.initials: MJ
authors.lastname: Patil
authors.forename: Taleen
authors.initials: T
authors.lastname: Hanania
authors.forename: Heather S
authors.initials: HS
authors.lastname: Hain
authors.forename: Scott F
authors.initials: SF
authors.lastname: Davis
authors.forename: Sam A
authors.initials: SA
authors.lastname: Malekiani
authors.forename: Andrew
authors.initials: A
authors.lastname: Hu
authors.forename: Roy
authors.initials: R
authors.lastname: Sucholeiki
authors.forename: Darrell
authors.initials: D
authors.lastname: Nix
authors.forename: Irving
authors.initials: I
authors.lastname: Sucholeiki
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000627:therapeutic use*; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D004195:Disease Models, Animal; D000077206:Gabapentin; D006930:Hyperalgesia / Q000188:drug therapy*; D007211:Indoles / Q000627:therapeutic use*; D020778:Matrix Metalloproteinase 2; D061965:Matrix Metalloproteinase Inhibitors / Q000627:therapeutic use*; D009437:Neuralgia / Q000188:drug therapy*; D011422:Propionates / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves; D013876:Thiophenes / Q000627:therapeutic use*; D014276:Trigeminal Nerve; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use*
chemical_list: C000604039:AQU-118; D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D007211:Indoles; D061965:Matrix Metalloproteinase Inhibitors; D011422:Propionates; D013876:Thiophenes; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D020778:Matrix Metalloproteinase 2