R-phenibut binds to the α2-δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects

Liga Zvejniece, Edijs Vavers, Baiba Svalbe, Grigory Veinberg, Kristina Rizhanova, Vilnis Liepins, Ivars Kalvinsh, Maija Dambrova

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

Phenibut is clinically used anxiolytic, mood elevator and nootropic drug. R-phenibut is responsible for the pharmacological activity of racemic phenibut, and this activity correlates with its binding affinity for GABAB receptors. In contrast, S-phenibut does not bind to GABAB receptors. In this study, we assessed the binding affinities of R-phenibut, S-phenibut, baclofen and gabapentin (GBP) for the α2-δ subunit of the voltage-dependent calcium channel (VDCC) using a subunit-selective ligand, radiolabelled GBP. Binding experiments using rat brain membrane preparations revealed that the equilibrium dissociation constants (Kis) for R-phenibut, S-phenibut, baclofen and GBP were 23, 39, 156 and 0.05 μM, respectively. In the pentylenetetrazole (PTZ)-induced seizure test, we found that at doses up to 100 mg/kg, R-phenibut did not affect PTZ-induced seizures. The anti-nociceptive effects of R-phenibut were assessed using the formalin-induced paw-licking test and the chronic constriction injury (CCI) of the sciatic nerve model. Pre-treatment with R-phenibut dose-dependently decreased the nociceptive response during both phases of the test. The anti-nociceptive effects of R-phenibut in the formalin-induced paw-licking test were not blocked by the GABAB receptor-selective antagonist CGP35348. In addition, treatment with R- and S-phenibut alleviated the mechanical and thermal allodynia induced by CCI of the sciatic nerve. Our data suggest that the binding affinity of R-phenibut for the α2-δ subunit of the VDCC is 4 times higher than its affinity for the GABAB receptor. The anti-nociceptive effects of R-phenibut observed in the tests of formalin-induced paw licking and CCI of the sciatic nerve were associated with its effect on the α2-δ subunit of the VDCC rather than with its effects on GABAB receptors. In conclusion, our results provide experimental evidence for GBP-like, anti-nociceptive properties of R-phenibut, which might be used clinically to treat neuropathic pain disorders.

Original languageEnglish
Pages (from-to)23-29
Number of pages7
JournalPharmacology Biochemistry and Behavior
Volume137
DOIs
Publication statusPublished - 11 Aug 2015

Keywords*

  • CCI of the sciatic nerve
  • CGP35348
  • Formalin-induced paw-licking test
  • Gabapentin
  • R-phenibut
  • The α-δ subunit of the voltage-dependent calcium channel

Field of Science*

  • 3.1 Basic medicine

Publication Type*

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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