Presynaptic inhibition of primary afferents by depolarization: observations supporting nontraditional mechanisms

Abstract

Primary afferent neurotransmission is the fundamental first step in the central processing of sensory stimuli and is controlled by pre- and postsynaptic inhibitory mechanisms. Presynaptic inhibition (PSI) is probably the more powerful form of inhibitory control in all primary afferent fibers. A major mechanism producing afferent PSI is via a channel-mediated depolarization of their intraspinal terminals, which can be recorded extracellularly as a dorsal root potential (DRP). Based on measures of DRP latency it has been inferred that this primary afferent depolarization (PAD) of low-threshold afferents is mediated by minimally trisynaptic pathways with pharmacologically identified GABAergic interneurons forming last-order axo-axonic synapses onto afferent terminals. There is still no "squeaky clean" evidence of this organization. This paper describes recent and historical work that supports the existence of PAD occurring by more direct pathways and with a complex pharmacology that questions the proprietary role of GABA and GABA(A) receptors in this process. Cholinergic transmission in particular may contribute significantly to PAD, including via direct release from primary afferents.

Endogenously released 5-HT inhibits A and C fiber-evoked synaptic transmission in the rat spinal cord by the facilitation of GABA/glycine and 5-HT release via 5-HT2A and 5-HT3 receptors

“…Furthermore, ketanserin also blocked 5-HT and α-Me-5-HT (a 5-HT2 receptor agonist)-evoked depolarization of the basal ventral root, suggesting that these excitatory effects on motoneurons were also mediated via 5-HT2A receptors. The depolarization of motoneurons may, at least in part, contribute to the inhibitory effects of 5-HT because marked depolarization in the spinal networks can inhibit signal transduction (Hochman et al, 2010). The detection of 5-HT3 receptor mRNA in the brain stem, from which descending serotonergic fibers originate (Fonseca et al, 2001), supports our hypothesis that 5-HT3 receptors exist in the nerve terminals of descending fibers in the spinal cord.…”

Peripheral type of choline acetyltransferase: Biological and evolutionary implications for novel mechanisms in cholinergic system

“…In reasonable accord with this fact, pChAT-positive staining occurs in dorsal roots extending from DRG neurons to the spinal cord. Within the spinal cord, pChAT-labeled fibers are seen mainly in the dorsal funiculus as part of ascending primary afferents to the nuclei cuneatus and gracilis (Kimura, unpublished data), and partly in deep layers of the dorsal horn (Hochman et al, 2010). Our experiment using dorsal root ligation shows that pChAT is transported centripetally from DRG neurons to the spinal cord, implying that pChAT may function within axons or presynaptic terminals in the spinal cord .…”

“…Both the large and small DRG neurons are proved to express pChAT mRNA but never cChAT mRNA . By immunohistochemistry, all DRG neurons are found positive for pChAT, though varying in staining intensity (small neurons often stain intensely, while large ones faintly) Hochman et al, 2010;Hanada, unpublished data). These results together with our Western blot analysis clearly demonstrate that all DRG neurons express pChAT but not cChAT.…”

Bicuculline-Sensitive Primary Afferent Depolarization Remains after Greatly Restricting Synaptic Transmission in the Mammalian Spinal Cord

“…Large-diameter afferents preferentially express the vesicular ACh transporter as well as acetylcholinesterase (Willis and Coggeshall, 1991;Tata et al, 2004;Bellier and Kimura, 2007). Primary afferents also contain bicuculline-sensitive ␣9 and ␣10 nicotinic ACh receptor subunits (Rothlin et al, 1999;Lips et al, 2002;Alexander et al, 2007) and preliminary results demonstrate reduction in DRP amplitude by nicotinic receptor antagonists with reported actions on ␣9 receptors (Hochman et al, 2010).…”