The drug baclofen is a potential treatment for severe tinnitus, but its action in relieving tinnitus is not known. Baclofen is available as an approved drug only in racemic form with about equal content of the two enantiomers. In the present paper we show that l-baclofen causes a considerable (40.7%) suppression of the amplitude of the second peak in the click-evoked response from the cochlear nucleus. Bipolar recordings from the external nucleus of the inferior colliculus showed that l-baclofen caused a reduction in the amplitude of three or four distinct peaks in this response. d-Baclofen had no detectable effect on the response from the cochlear nucleus, and had only a slight effect on one component of the response from the external nucleus of the inferior colliculus. The demonstrated effect of l-baclofen on excitation in the ascending auditory pathway indicates that this drug may be a potential treatment for hyperactive auditory disorders such as tinnitus and hyperacusis.
FrommGHTerrenceCFChatthaASGlassJD. Baclofen in trigeminal neuralgia. Its effect on the spinal trigeminal nucleus: a pilot study. Arch Neurol1980; 37: 768–71.
2.
YoungRRDelwaidePJ. Drug therapy: spasticity. N Engl J Med1981; 304: 96–9.
3.
KeberleHFaigleJW. Synthesis and structure-activity relationship of the gamma-aminobutyric acid derivatives. In: BirkmayerV, ed. Spasticity — a topical survey. Vienna, Austria: Hans Huber Publishers, 1971: 90–3.
4.
DunlapK. Two types of gamma-aminobutyric acid receptor on embryonic sensory neurones. Br J Pharmacol1981; 74: 579–85.
5.
DesarmenienMFeltzPOcchipintiGSantangeloFSchlichterT. Co-existence of GABAa and GABAb receptors of Aδ and C primary afferents. Br J Pharmacol1984; 81: 327–33.
6.
CherubiniENorthRA. Inhibition of calcium spikes and transmitter release by gamma-aminobutyric acid in the guinea pig myenteric plexus. Br J Pharmacol1984; 82: 101–5.
7.
RobertsonBTaylorWR. Effects of gamma-aminobutyric acid and (–)baclofen on calcium and potassium currents in cat dorsal root ganglion neurones in vitro. Br J Pharmacol1986; 89: 661–72.
8.
GreenKACottrellGA. Baclofen and calcium channels in dorsal root ganglion neurones. Neurosci Lett1987; 29(supp1 88).
9.
FormentiASansomeV. Inhibitory action of acetylcholine, baclofen, and GTP-gamma-S on calcium channels in adult rat sensory neurons. Neurosci Lett1991; 131: 267–72.
10.
AultBNadlerJV. Baclofen selectivity inhibits transmission at synapses made by axons of CA3 pyramidal cells in the hippocampal slice. J Pharmacol Exp Ther1982; 223: 291–7.
11.
DaviesJ. Selective depression of synaptic excitation in cat spinal neurones by baclofen: an iontophoretic study. Br J Pharmacol1981; 72: 373–84.
12.
BoweryNGHillDRHudsonAL. (–)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature1980; 283: 92–4.
NewberryNRNicollRA. Direct hyperpolarizing action of baclofen on hippocampal pyramidal cells. Nature1984; 308: 450–2.
15.
GähwilerBHBrownDA. GABAb-receptor-activated K+ current in voltage-clamped CA3 pyramidal cells in hippocampal cultures. Proc Natl Acad Sci USA1985; 82: 1558–62.
16.
DutarPNicollRA. A physiological role for GABAb receptors in the central nervous system. Nature1988; 332: 156–8.
17.
SolteszIHabyMLerescheNCrunelliV. The GABAb antagonist phaclofen inhibits the late K+ dependent IPSP in cat and rat thalamic and hippocampal neurones. Brain Res1988; 448: 351–4.
18.
PittalugaAAsaroDPellegriniGRaiteriM. Studies of 3H-GABA and endogenous GABA release in rat cerebral cortex suggest the presence of autoreceptors of the GABAb type. Eur J Pharmacol1987; 144: 45–52.
19.
WaldmeierPCWickiPFeldtrauerJJBaumannPD. Potential involvement of a baclofen-sensitive autoreceptor in the modulation of the release of endogenous GABA from rat brain slices in vitro. Naunyn Schmiedebergs Arch Pharmacol1988; 337: 289–95.
20.
WaldmeierPCStocklinKFeldtrauerJJ. Systemic administration of baclofen and the GABAb receptors and transmitter release. In: BoweryNGBittigerHOlpeHR, eds. GABAb receptors in mammalian function. Chichester, England: Wiley, 1990: 63–80.
21.
BoweryNG. GABAb receptor pharmacology. Annu Rev Pharmacol Toxicol1993; 33: 109–47.
22.
OlpeHRDemievilleHBaltzerV. The biological activity of d and l baclofen. Eur J Pharmacol1978; 52: 133–6.
23.
WilsonPRYakshTL. Baclofen is antinociceptive in the spinal intrathecal space of animals. Eur J Pharmacol1978; 51: 323–30.
24.
SmithDFVestergaardP. The role of monoamines for the central effects of baclofen on behaviour of rats. J Neural Transm1979; 46: 215–23.
25.
CurtisDRLodgeDBornsteinJCPeetMJ. Selective effects of (–)-baclofen on spinal synaptic transmission in the cat. Exp Brain Res1981; 42: 158–70.
26.
FrommGHSatoKNakataM. The action of GABAb antagonists in the trigeminal nucleus of the rat. Neuropharmacology1992; 31: 475–80.
27.
FrommGHShibuyaTNakataMTerrenceCF. Effects of d-baclofen and l-baclofen on the trigeminal nucleus. Neuropharmacology1990; 29: 249–54.
28.
FrommGHTerrenceCF. Comparison of l-baclofen and racemic baclofen in trigeminal neuralgia. Neurology1987; 37: 1725–8.
29.
LeesAJClarkeCRAHarrisonMJ. Hallucinations after withdrawal of baclofen. Lancet1977; 8016: 858.
30.
Van NoortJ. The structure and connections of the inferior colliculus. An investigation of lower auditory system. Assen, the Netherlands: Van Gorcum and Company, 1969.
31.
AitkinLMDickhausHSchultWZimmermannM. External nucleus of inferior colliculus: auditory and spinal somatosensory afferents and their interactions. J Neurophysiol1978; 41: 837–47.
32.
AitkinL. The auditory midbrain, structure and function in the central auditory pathway. Clifton, NJ: Human Press, 1986.
33.
GraybielAM. Some fiber pathways related to the posterior thalamic region in the cat. Brain Behav Evol1972; 6: 363–93.
34.
MøllerARMøllerMBYokotaM. Some forms of tinnitus may involve the extralemniscal auditory pathway. Laryngoscope1992; 102: 1165–71.
35.
PiersonMSmithKLSwannJW. A slow NMDA-mediated synaptic potential underlies seizures originating from midbrain. Brain Res1989; 486: 381–6.
KesnerRP. Subcortical mechanisms of audiogenic seizures. Exp Neurol1966; 15: 195–205.
38.
FryeGDMcCownTJBreeseGRPetersonSL. GABA-ergic modulation of inferior colliculus excitability: role in the ethanol withdrawal audiogenic seizures. J Pharmacol Exp Ther1986; 237: 478–85.
39.
CasparyDMRybakLPFaingoldCL. Baclofen reduces tone evoked activity of cochlear nucleus neurons. Hear Res1984; 13: 113–22.
40.
SzczepaniakWSMøllerAR. Interaction between auditory and somatosensory systems: a study of evoked potentials in the inferior colliculus. Electroencephalogr Clin Neurophysiol1993; 88: 508–15.
41.
MøllerAR. On the origin of the compound action potentials (N1N2) of the cochlea of the rat. Exp Neurol1983; 80: 633–44.
