title: GABAB receptors inhibit low-voltage activated and high-voltage activated Ca(2+) channels in sensory neurons via distinct mechanisms.
abstract: Growing evidence suggests that mammalian peripheral somatosensory neurons express functional receptors for gamma-aminobutyric acid, GABAA and GABAB. Moreover, local release of GABA by pain-sensing (nociceptive) nerve fibres has also been suggested. Yet, the functional significance of GABA receptor triggering in nociceptive neurons is not fully understood. Here we used patch-clamp recordings from small-diameter cultured DRG neurons to investigate effects of GABAB receptor agonist baclofen on voltage-gated Ca(2+) currents. We found that baclofen inhibited both low-voltage activated (LVA, T-type) and high-voltage activated (HVA) Ca(2+) currents in a proportion of DRG neurons by 22% and 32% respectively; both effects were sensitive to Gi/o inhibitor pertussis toxin. Inhibitory effect of baclofen on both current types was about twice less efficacious as compared to that of the μ-opioid receptor agonist DAMGO. Surprisingly, only HVA but not LVA current modulation by baclofen was partially prevented by G protein inhibitor GDP-β-S. In contrast, only LVA but not HVA current modulation was reversed by the application of a reducing agent dithiothreitol (DTT). Inhibition of T-type Ca(2+) current by baclofen and the recovery of such inhibition by DTT were successfully reconstituted in the expression system. Our data suggest that inhibition of LVA current in DRG neurons by baclofen is partially mediated by an unconventional signaling pathway that involves a redox mechanism. These findings reinforce the idea of targeting peripheral GABA receptors for pain relief.
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050011, PR China.
authors.forename: Dongyang
authors.initials: D
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050011, PR China.
authors.forename: Sha
authors.initials: S
authors.lastname: Huang
authors.affiliation: Faculty of Medicine and Health, University of Leeds, Leeds, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Peers
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050011, PR China.
authors.forename: Xiaona
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050011, PR China. Electronic address: zhanghl@hebmu.edu.cn.
authors.forename: Hailin
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Hebei Medical University, Shijiazhuang, 050011, PR China; School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, UK. Electronic address: N.Gamper@leeds.ac.uk.
authors.forename: Nikita
authors.initials: N
authors.lastname: Gamper
mesh_terms: D000818:Animals; D001418:Baclofen / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D004229:Dithiothreitol / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D058786:GABA-B Receptor Agonists / Q000494:pharmacology*; D005727:Ganglia, Spinal; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D059225:Nociception / Q000502:physiology; D010146:Pain / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D037342:Pertussis Toxin / Q000494:pharmacology; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D013873:Thionucleotides / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D020747:Calcium Channels, T-Type; D058786:GABA-B Receptor Agonists; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D013873:Thionucleotides; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D006153:Guanosine Diphosphate; D005680:gamma-Aminobutyric Acid; C023427:guanosine 5'-O-(2-thiodiphosphate); D037342:Pertussis Toxin; D001418:Baclofen; D004229:Dithiothreitol
keywords: Baclofen; GABA(B) receptors; Nociceptor; Opioid receptor; Redox mechanisms; T-type Ca(2+) channels