title: Clinically relevant concentration of pregabalin has no acute inhibitory effect on excitation of dorsal horn neurons under normal or neuropathic pain conditions: An intracellular calcium-imaging study in spinal cord slices from adult rats.
abstract: Pregabalin is thought to exert its therapeutic effect in neuropathic pain via binding to α2δ-1 subunits of voltage-gated calcium (Ca(2+)) channels. However, the exact analgesic mechanism after its binding to α2δ-1 subunits remains largely unknown. Whether a clinical concentration of pregabalin (≈10μM) can cause acute inhibition of dorsal horn neurons in the spinal cord is controversial. To address this issue, we undertook intracellular Ca(2+)-imaging studies using spinal cord slices with an intact attached L5 dorsal root, and examined if pregabalin acutely inhibits the primary afferent stimulation-evoked excitation of dorsal horn neurons in normal rats and in rats with streptozotocin-induced painful diabetic neuropathy. Under normal conditions, stimulation of a dorsal root evoked Ca(2+) signals predominantly in the superficial dorsal horn. Clinically relevant (10μM) and a very high concentration of pregabalin (100μM) did not affect the intensity or spread of dorsal root stimulation-evoked Ca(2+) signals, whereas an extremely high dose of pregabalin (300μM) slightly but significantly attenuated Ca(2+) signals in normal rats and in diabetic neuropathic (DN) rats. There was no difference between normal rats and DN rats with regard to the extent of signal attenuation at all concentrations tested. These results suggest that the activity of dorsal horn neurons in the spinal cord is not inhibited acutely by clinical doses of pregabalin under normal or DN conditions. It is very unlikely that an acute inhibitory action in the dorsal horn is the main analgesic mechanism of pregabalin in neuropathic pain states.
authors.affiliation: Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan. Electronic address: baba@med.niigata-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Baba
authors.affiliation: Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan.
authors.forename: Andrey B
authors.initials: AB
authors.lastname: Petrenko
authors.affiliation: Division of Medical Technology, Niigata University Graduate School of Health Sciences, 2-746 Asahimachi-dori, Chuo-ku, Niigata 951-8518, Japan.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Fujiwara
mesh_terms: D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects*; D003929:Diabetic Neuropathies / Q000139:chemically induced / Q000150:complications*; D004558:Electric Stimulation; D008297:Male; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D017288:Pain Threshold / Q000187:drug effects; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism; D000069583:Pregabalin / Q000008:administration & dosage*; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D013126:Spinal Nerve Roots / Q000503:physiopathology; D013311:Streptozocin
chemical_list: D000700:Analgesics; D001786:Blood Glucose; D000069583:Pregabalin; D013311:Streptozocin
keywords: Acute effect; Ca(2+)-imaging; Clinically relevant concentration; Diabetic neuropathic rat; Pregabalin; Spinal cord