Interaction of gamma-aminobutyric acid receptor type B receptors and calcium channels in nociceptive transmission studied in the mouse hemisected spinal cord in vitro: withdrawal symptoms related to baclofen treatment

Neurosci Lett. 2004 May 6;361(1-3):72-5. doi: 10.1016/j.neulet.2003.12.009.

Abstract

An in vitro mouse hemisected spinal cord was used to characterize the gamma-aminobutyric acid receptor type B (GABA(B)) modulation of the ventral root potential (VRP) in response to electrical stimulation of the dorsal root (DR). Low-intensity (LI) and high-intensity (HI) stimulation induced VRPs with progressively higher amplitude and duration. Repetitive HI-stimulation of the DR (1-10 Hz) produced windup. The selective GABA(B) receptor agonist, CGP35024, inhibited the VRPs in a dose-dependent manner. The inhibitory action of CGP35024 was blocked by CGP52432, a potent GABA(B) receptor antagonist. Following washout of the GABA(B) receptor agonist, VRPs and windup were significantly enhanced. The rebound increase of the VRP following removal of CGP35024 was also blocked by the GABA(B) receptor antagonist, CGP52432. This phenomenon is not linked to receptor desensitization, but rather due to GABA(B) receptor-induced hyperactivity of N-, P/Q-type Ca(2+) channels, as omega-CgTx GVIA and MVIIC abolished/prevented the increase. The 'rebound' enhancement of the spinal transmission after exposure to GABA(B) agonists sheds light on the possible mechanism of the severe withdrawal effects after abrupt termination of baclofen treatment in patients suffering from multiple sclerosis.

MeSH terms

  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Afferent Pathways / drug effects
  • Afferent Pathways / metabolism
  • Animals
  • Baclofen / pharmacology*
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels / drug effects
  • Calcium Channels / metabolism*
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • GABA Agonists / pharmacology
  • GABA Antagonists / pharmacology
  • GABA-B Receptor Agonists
  • GABA-B Receptor Antagonists
  • In Vitro Techniques
  • Mice
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology
  • Neurons, Afferent / drug effects
  • Neurons, Afferent / metabolism
  • Nociceptors / drug effects
  • Nociceptors / metabolism*
  • Pain / drug therapy
  • Pain / metabolism
  • Pain / physiopathology
  • Receptors, GABA-B / metabolism*
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism*
  • Spinal Cord / physiopathology
  • Spinal Nerve Roots / drug effects
  • Spinal Nerve Roots / metabolism
  • Spinal Nerve Roots / physiology
  • Substance Withdrawal Syndrome / metabolism*
  • Substance Withdrawal Syndrome / physiopathology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology

Substances

  • Calcium Channel Blockers
  • Calcium Channels
  • GABA Agonists
  • GABA Antagonists
  • GABA-B Receptor Agonists
  • GABA-B Receptor Antagonists
  • Receptors, GABA-B
  • Baclofen