Labetalol facilitates GABAergic transmission to rat periaqueductal gray neurons via antagonizing β1-adrenergic receptors - A possible mechanism underlying labetalol-induced analgesia

Cheng Xiao, Chunyi Zhou, Glen Atlas, Ellise S. Delphin, Jiang Hong Ye

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Labetalol, a combined α1, β1, and β2 adrenoceptor-blocking drug, has been shown to have analgesic properties in vivo. To determine the underlying mechanisms, we examined its effects on GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) and spontaneous firings of rat ventrolateral periaqueductal gray (PAG) neurons, either mechanically dissociated, or in acute brain slices. These PAG neurons mediate opioid-mediated analgesia and pain transmission and are under tonic control of GABAergic interneurons. An increase in GABAergic transmission to these neurons yields an inhibitory hyperpolarized state and may interrupt pain signal transmission. Using patch clamp techniques, we found that labetalol reversibly increases the frequency of sIPSCs without changing their mean amplitude. This indicates that labetalol enhances GABAergic synaptic transmission by a presynaptic mechanism. Metoprolol, a specific β1-adrenoceptor antagonist, also reversibly enhanced sIPSC frequency. In the presence of metoprolol, labetalol-induced increase in sIPSC frequency was significantly attenuated or even abolished. These results suggest that labetalol shares the same pathway as metoprolol in enhancing GABAergic transmission via an inhibition of presynaptic β1-adrenoceptors. We further showed that labetalol reversibly reduced the firing rate of PAG neurons. This reduction was significantly attenuated in the presence of bicuculline, a selective antagonist of GABAA receptors. These data indicate that labetalol-induced inhibition of PAG cell firing is attributable to its potentiation of GABAergic transmission. Based on these data, we postulate that labetalol-induced analgesia is at least in part ascribed to its antagonistic effects on presynaptic β1-adrenoceptors.

Original languageEnglish (US)
Pages (from-to)34-43
Number of pages10
JournalBrain Research
Volume1198
DOIs
StatePublished - Mar 10 2008
Externally publishedYes

Fingerprint

Labetalol
Periaqueductal Gray
Analgesia
Adrenergic Receptors
Neurons
Inhibitory Postsynaptic Potentials
Metoprolol
GABA-A Receptors
Pain
Bicuculline
Patch-Clamp Techniques
Interneurons
Synaptic Transmission
Opioid Analgesics
Analgesics
Brain

Keywords

  • β1-adrenergic receptors
  • Analgesia
  • Brain slices
  • Firing
  • GABAergic transmission
  • IPSCs
  • Labetalol
  • Periaqueductal gray
  • Rat

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Developmental Biology
  • Molecular Biology

Cite this

Labetalol facilitates GABAergic transmission to rat periaqueductal gray neurons via antagonizing β1-adrenergic receptors - A possible mechanism underlying labetalol-induced analgesia. / Xiao, Cheng; Zhou, Chunyi; Atlas, Glen; Delphin, Ellise S.; Ye, Jiang Hong.

In: Brain Research, Vol. 1198, 10.03.2008, p. 34-43.

Research output: Contribution to journalArticle

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abstract = "Labetalol, a combined α1, β1, and β2 adrenoceptor-blocking drug, has been shown to have analgesic properties in vivo. To determine the underlying mechanisms, we examined its effects on GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) and spontaneous firings of rat ventrolateral periaqueductal gray (PAG) neurons, either mechanically dissociated, or in acute brain slices. These PAG neurons mediate opioid-mediated analgesia and pain transmission and are under tonic control of GABAergic interneurons. An increase in GABAergic transmission to these neurons yields an inhibitory hyperpolarized state and may interrupt pain signal transmission. Using patch clamp techniques, we found that labetalol reversibly increases the frequency of sIPSCs without changing their mean amplitude. This indicates that labetalol enhances GABAergic synaptic transmission by a presynaptic mechanism. Metoprolol, a specific β1-adrenoceptor antagonist, also reversibly enhanced sIPSC frequency. In the presence of metoprolol, labetalol-induced increase in sIPSC frequency was significantly attenuated or even abolished. These results suggest that labetalol shares the same pathway as metoprolol in enhancing GABAergic transmission via an inhibition of presynaptic β1-adrenoceptors. We further showed that labetalol reversibly reduced the firing rate of PAG neurons. This reduction was significantly attenuated in the presence of bicuculline, a selective antagonist of GABAA receptors. These data indicate that labetalol-induced inhibition of PAG cell firing is attributable to its potentiation of GABAergic transmission. Based on these data, we postulate that labetalol-induced analgesia is at least in part ascribed to its antagonistic effects on presynaptic β1-adrenoceptors.",
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T1 - Labetalol facilitates GABAergic transmission to rat periaqueductal gray neurons via antagonizing β1-adrenergic receptors - A possible mechanism underlying labetalol-induced analgesia

AU - Xiao, Cheng

AU - Zhou, Chunyi

AU - Atlas, Glen

AU - Delphin, Ellise S.

AU - Ye, Jiang Hong

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