Activaton of GABAB receptor inhibits the excitability of rat small diameter trigeminal root ganglion neurons.
A selective GABA(B) receptor agonist, baclofen, is known to suppress neuropathic pain. In the present study, we investigated the effect of baclofen on the excitability of trigeminal root ganglion (TRG) neurons by using the whole cell and perforated patch-clamp recording techniques. Under voltage-clamp (V(h)=-60 mV), voltage-dependent K(+) currents were recorded in the small diameter TRG neurons (<30 microm) and isolated by blocking Na(+) and Ca(2+) currents with appropriate ion replacement. Separation of the K(+) current components was achieved by the response to variation in the conditioning voltage. Two distinct K(+) current components, a transient (I(A)) and a sustained (I(k)), were identified. Baclofen significantly increased I(A) by 74.8% (50 microM) and in a dose-dependent manner (1-50 microM). Similarly, I(K) was also enhanced by baclofen administration (41.8%: 50 microM). The relative amplitude of potentiation of I(A) was significantly higher than that of I(K) (P<0.05). Baclofen-sensitive I(A) and I(K) currents were antagonized by K(+) channel blockers, 4-aminopyridine (4-AP) and tetraethylammonium (TEA). The augmentation of K(+) currents was antagonized by 3-amino-2-(4-chlorophenyl)-2-hydroxypropylsulfonic acid (saclofen; GABA(B) antagonist). In the current clamp mode, the resting membrane potential was -62+/-1.6 mV (n=24). Hyperpolarization of the membrane potential was elicited by baclofen (10-50 microM), and the response was associated with a decrease in the input resistance. Baclofen induced-hyperpolarization was blocked by saclofen (100 microM). In the presence of both 4-AP and TEA, no significant changes in membrane potential induced by baclofen application were observed. In the presence of BaCl(2), baclofen-evoked hyperpolarization with decreased resistance was observed. During application of baclofen, the firing rate of the action potentials by depolarizing step pulses was decreased. Application of baclofen reduced action potential duration evoked by a depolarization current pulse.These results indicated that activation of GABA(B) receptors inhibits the excitability of rat small diameter TRG neurons and this inhibitory action is mediated by potentiation of voltage-dependent K(+) currents. We therefore concluded that modification of nociceptive transmission in the trigeminal system by activation of GABA(B) receptors occurs at the level of small TRG neuron cell bodies and/or their primary afferent terminals, which are potential targets of analgesia by baclofen.
Takeda
M
M
Department of Physiology, School of Dentistry at Tokyo, Nippon Dental University, 1-9-20, Fujimi-cho, Chiyoda-ku, Tokyo, 102-8159, Japan. m-takeda@tokyo.ndu.ac.jp
Tanimoto
T
T
Ikeda
M
M
Kadoi
J
J
Matsumoto
S
S
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002478:Cells, Cultured; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000503:physiopathology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D018080:Receptors, GABA-B / Q000187:drug effects / Q000378:metabolism*; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000502:physiology*
D018755:GABA Agonists; D018756:GABA Antagonists; D026902:Potassium Channel Blockers; D018080:Receptors, GABA-B; D001418:Baclofen