Pain information reaches the spinal cord via unmyelinated or thinly myelinated central processes of the small diameter nociceptors located in the dorsal root ganglia. Nociceptive signals en route to the brain are then integrated at the level of the dorsal horn of the spinal cord where synapses with second order sensory neurons are located. These synapses are the target of a complex network of spinal interneurons that is mainly localized in lamina II (substantia gelatinosa) of the gray matter. Transmission/modulation of nociceptive inputs in lamina II is mediated by an impressive number of neurotransmitters. The low molecular weight glutamate, GABA and glycine are responsible for fast neurotransmission and likely involved in rapid adaptive responses to noxious stimuli. The high molecular weight peptides, instead, produce slower and long lasting responses that may drastically influence chronic pain. Peptidergic nociceptive fibers also contain th e trophic factors BDNF and GDNF that are segregated into two different types of central projections, respectively containing somatostatin and substance P. I will resume here the recent work that led unravel the circuitry made by BDNF- and GDNFexpressing nociceptors. I will also provide structural and functional evidence for the neurotransmitter role of BDNF and GDNF in dorsal horn, specifically showing that GDNF, released from peptidergic primary afferent fibers, inhibits the GFRα1-RET-expressing non-peptidergic IB4-positive primary afferent fibers in lamina II. It was suggested that the main site for pain modality discrimination is localized in nociceptors, rather than in spinal or supraspinal sites. In this respect, the peptidergic to non-peptidergic nociceptor communication mediated by GDNF may serve as a pre-synaptic mechanism that, under normal conditions, preserves the specificity of the nociceptive input, and raises pain thresholds in lamina II during chronic inflammation.
Cross-talk of peptidergic to non-peptidergic nociceptive fiber projections in the dorsal horn
MERIGHI, Adalberto
2013-01-01
Abstract
Pain information reaches the spinal cord via unmyelinated or thinly myelinated central processes of the small diameter nociceptors located in the dorsal root ganglia. Nociceptive signals en route to the brain are then integrated at the level of the dorsal horn of the spinal cord where synapses with second order sensory neurons are located. These synapses are the target of a complex network of spinal interneurons that is mainly localized in lamina II (substantia gelatinosa) of the gray matter. Transmission/modulation of nociceptive inputs in lamina II is mediated by an impressive number of neurotransmitters. The low molecular weight glutamate, GABA and glycine are responsible for fast neurotransmission and likely involved in rapid adaptive responses to noxious stimuli. The high molecular weight peptides, instead, produce slower and long lasting responses that may drastically influence chronic pain. Peptidergic nociceptive fibers also contain th e trophic factors BDNF and GDNF that are segregated into two different types of central projections, respectively containing somatostatin and substance P. I will resume here the recent work that led unravel the circuitry made by BDNF- and GDNFexpressing nociceptors. I will also provide structural and functional evidence for the neurotransmitter role of BDNF and GDNF in dorsal horn, specifically showing that GDNF, released from peptidergic primary afferent fibers, inhibits the GFRα1-RET-expressing non-peptidergic IB4-positive primary afferent fibers in lamina II. It was suggested that the main site for pain modality discrimination is localized in nociceptors, rather than in spinal or supraspinal sites. In this respect, the peptidergic to non-peptidergic nociceptor communication mediated by GDNF may serve as a pre-synaptic mechanism that, under normal conditions, preserves the specificity of the nociceptive input, and raises pain thresholds in lamina II during chronic inflammation.
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