title: A mixed Ca2+ channel blocker, A-1264087, utilizes peripheral and spinal mechanisms to inhibit spinal nociceptive transmission in a rat model of neuropathic pain.
abstract: N-, T- and P/Q-type voltage-gated Ca(2+) channels are critical for regulating neurotransmitter release and cellular excitability and have been implicated in mediating pathological nociception. A-1264087 is a novel state-dependent blocker of N-, T- and P/Q-type channels. In the present studies, A-1264087 blocked (IC50 = 1.6 μM) rat dorsal root ganglia N-type Ca(2+) in a state-dependent fashion. A-1264087 (1, 3 and 10 mg/kg po) dose-dependently reduced mechanical allodynia in rats with a spinal nerve ligation (SNL) injury. A-1264087 (4 mg/kg iv) inhibited both spontaneous and mechanically evoked activity of spinal wide dynamic range (WDR) neurons in SNL rats but had no effect in uninjured rats. The inhibitory effect on WDR neurons remained in spinally transected SNL rats. Injection of A-1264087 (10 nmol/0.5 μl) into the spinal cord reduced both spontaneous and evoked WDR activity in SNL rats. Application of A-1264087 (300 nmol/20 μl) into the receptive field on the hindpaw attenuated evoked but not spontaneous firing of WDR neurons. Using electrical stimulation, A-1264087 (4 mg/kg iv) inhibited Aδ- and C-fiber evoked responses and after-discharge of WDR neurons in SNL rats. These effects by A-1264087 were not present in uninjured rats. A-1264087 moderately attenuated WDR neuron windup in both uninjured and SNL rats. In summary, these results indicate that A-1264087 selectively inhibited spinal nociceptive transmission in sensitized states through both peripheral and central mechanisms.
authors.affiliation: Neuroscience Research, AbbVie, North Chicago, Illinos.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Katharine L
authors.initials: KL
authors.lastname: Chu
authors.forename: Chang Z
authors.initials: CZ
authors.lastname: Zhu
authors.forename: Wende
authors.initials: W
authors.lastname: Niforatos
authors.forename: Andrew
authors.initials: A
authors.lastname: Swensen
authors.forename: Xenia
authors.initials: X
authors.lastname: Searle
authors.forename: Lance
authors.initials: L
authors.lastname: Lee
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Steve
authors.initials: S
authors.lastname: McGaraughty
mesh_terms: D000200:Action Potentials; D000279:Administration, Cutaneous; D000777:Anesthetics / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D020128:Inhibitory Concentration 50; D007278:Injections, Spinal; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D059225:Nociception / Q000187:drug effects*; D010525:Peripheral Nerves / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves / Q000187:drug effects* / Q000502:physiology
chemical_list: D000777:Anesthetics; D053961:Azabicyclo Compounds; D002121:Calcium Channel Blockers; C000591006:N2-methyl-N-((2-(4-(trifluoromethyl)phenyl)octahydrocyclopenta(c)pyrrol-4-yl)leucinamide; D007930:Leucine
keywords: N-type Ca2+ channels; P/Q-type Ca2+ channels; T-type Ca2+ channels; neuropathic pain; spinal cord