Are baclofen-sensitive GABAB receptors present on primary afferent terminals of the spinal cord?

Abstract

The site of action of the antispastic drug baclofen has long been considered to reside in the spinal cord although supraspinal effects have also been reported. This beta-chlorophenyl derivative of the neurotransmitter gamma-aminobutyric acid (GABA) depresses both monosynaptic and polysynaptic transmission in the cord possibly through a decrease in transmitter release rather than by any antagonism at postsynaptic receptors. Recently, baclofen has been shown to be a selective ligand for a bicuculline-insensitive GABA receptor (GABAB) site that occurs widely in the mammalian central nervous system including the spinal cord. The apparent importance of the cord in the therapeutic effects of this drug prompted us to ask whether they involve GABAB site activation. As an initial step we have located these receptors by autoradiography, comparing them with classical GABAA sites. We report here that GABAB sites, unlike GABAA sites, are present in high concentrations in laminae I, II, III and IV of the dorsal horn and that after the neonatal administration of capsaicin this binding is reduced by 40-50%.

GABA, glutamate and substance P‐like immunoreactivity release: effects of novel GABAB antagonists

“…On the other hand, GABAB receptors mediate an increase in potassium or a decrease in calcium conductance, either of which could produce a decrease in neurotransmitter release (Bowery et al, 1980;Conzelmann et al, 1986;Pittaluga et al, 1987;Waldmeier et al, 1988a,b;Bonanno et al, 1989a;Malcangio & Bowery, 1993;Santiago et al, 1993). Both types of GABA receptors are located on the Ab and C afferent fibres (Singer & Placheta, 1980;Desarmenien et al, 1984;Price et al, 1984) which terminate predominantly in the substantia gelatinosa (Cervero & Iggo, 1980;Brown, 1982) suggesting that this inhibitory amino acid and its receptors may be involved in the modulation of nociception. In support of this theory, exogenous GABA and GABA receptor agonists have been reported to inhibit the release of putative nociceptive neurotransmitters and neuropeptides from central nerve endings Benoliel et al, 1992;Malcangio & Bowery, 1993;Pende et al, 1993).…”

Actions of the GABAB agonist, (−)‐baclofen, on neurones in deep dorsal horn of the rat spinal cord in vitro

“…This is located mainly in laminae 2 and 3, but laminae 1 and 4 also appear to have a considerable number of binding sites (Price et al, 1984). The effect of baclofen on spinal dorsal horn neurones is thus likely to be important in terms of its functional role.…”

Intrathecal Pumps

“…Its receptors are located in high concentration of laminas II and III of the dorsal gray matter horns of the spinal cord. 26 The actions of baclofen are mediated by G-proteins, and the presynaptic binding restricts calcium influx and postsynaptic binding increases potassium conductance resulting in hyperpolarization. 27,28 Not only does this decrease excitatory synaptic release of neurotransmitters such as aspartate and glutamate, but also substance P in nociceptive afferent nerve endings thought to cause painful flexor spasms.…”