title: Acetazolamide and midazolam act synergistically to inhibit neuropathic pain.
abstract: Treatment of neuropathic pain is a major clinical challenge that has been met with minimal success. After peripheral nerve injury, a decrease in the expression of the K-Cl cotransporter KCC2, a major neuronal Cl(-) extruder, leads to pathologic alterations in GABA(A) and glycine receptor function in the spinal cord. The down-regulation of KCC2 is expected to cause a reduction in Cl(-) extrusion capacity in dorsal horn neurons, which, together with the depolarizing efflux of HCO(3)(-) anions via GABA(A) channels, would result in a decrease in the efficacy of GABA(A)-mediated inhibition. Carbonic anhydrases (CA) facilitate intracellular HCO(3)(-) generation and hence, we hypothesized that inhibition of CAs would enhance the efficacy of GABAergic inhibition in the context of neuropathic pain. Despite the decrease in KCC2 expression, spinal administration of benzodiazepines has been shown to be anti-allodynic in neuropathic conditions. Thus, we also hypothesized that spinal inhibition of CAs might enhance the anti-allodynic effects of spinally administered benzodiazepines. Here, we show that inhibition of spinal CA activity with acetazolamide (ACT) reduces neuropathic allodynia. Moreover, we demonstrate that spinal co-administration of ACT and midazolam (MZL) act synergistically to reduce neuropathic allodynia after peripheral nerve injury. These findings indicate that the combined use of CA inhibitors and benzodiazepines may be effective in the clinical management of neuropathic pain in humans.
authors.affiliation: The University of Arizona School of Medicine, Department of Pharmacology, 1501 N Campbell Ave., Tucson, AZ 85724, USA University of Helsinki, Department of Biosciences and Neuroscience Center, PO Box 65, Helsinki FIN-00014, Finland.
authors.forename: Marina
authors.initials: M
authors.lastname: Asiedu
authors.forename: Michael H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: Kai
authors.initials: K
authors.lastname: Kaila
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Price
mesh_terms: D000086:Acetazolamide / Q000627:therapeutic use*; D018686:Anesthetics, Intravenous / Q000627:therapeutic use*; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006930:Hyperalgesia / Q000145:classification / Q000188:drug therapy / Q000209:etiology; D008297:Male; D008874:Midazolam / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D045442:Rotarod Performance Test / Q000379:methods; D013997:Time Factors
chemical_list: D018686:Anesthetics, Intravenous; D002257:Carbonic Anhydrase Inhibitors; D000086:Acetazolamide; D008874:Midazolam