Feed-Forward Inhibition: A Novel Cellular Mechanism for the Analgesic Effect of Substance P

Substance P (SP) is a neuropeptide well known for its contribution to pain transmission in the spinal cord, however, less is known about the possible modulatory effects of SP. A new study by Gu and colleagues, published in Molecular Pain (2005, 1:20), describes its potential role in feed-forward inhibition in lamina V of the dorsal horn of the spinal cord. This inhibition seems to function through a direct excitation of GABAergic interneurons by substance P released from primary afferent fibers and has a distinct temporal phase of action from the well-described glutamate-dependent feed-forward inhibition. It is believed that through this inhibition, substance P can balance nociceptive output from the spinal cord.

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Substance P-Driven Feed-Forward Inhibitory Activity in the Mammalian Spinal Cord

Molecular Pain ◽

10.1186/1744-8069-1-20 ◽

2005 ◽

Vol 1 ◽

pp. 1744-8069-1-20 ◽

Cited By ~ 11

Author(s):

Terumasa Nakatsuka ◽

Meng Chen ◽

Daisuke Takeda ◽

Christopher King ◽

Jennifer Ling ◽

...

Keyword(s):

Spinal Cord ◽

Substance P ◽

Dorsal Horn ◽

Sensory Processing ◽

Inhibitory Activity ◽

Primary Afferent ◽

Feed Forward ◽

Afferent Fibers ◽

Somatosensory Input ◽

Primary Afferent Fibers

In mammals, somatosensory input activates feedback and feed-forward inhibitory circuits within the spinal cord dorsal horn to modulate sensory processing and thereby affecting sensory perception by the brain. Conventionally, feedback and feed-forward inhibitory activity evoked by somatosensory input to the dorsal horn is believed to be driven by glutamate, the principle excitatory neurotransmitter in primary afferent fibers. Substance P (SP), the prototypic neuropeptide released from primary afferent fibers to the dorsal horn, is regarded as a pain substance in the mammalian somatosensory system due to its action on nociceptive projection neurons. Here we report that endogenous SP drives a novel form of feed-forward inhibitory activity in the dorsal horn. The SP-driven feed-forward inhibitory activity is long-lasting and has a temporal phase distinct from glutamate-driven feed-forward inhibitory activity. Compromising SP-driven feed-forward inhibitory activity results in behavioral sensitization. Our findings reveal a fundamental role of SP in recruiting inhibitory activity for sensory processing, which may have important therapeutic implications in treating pathological pain conditions using SP receptors as targets.

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Projections of primary afferent fibers to last-order premotor interneurons in the lumbar spinal cord of rats

Brain Research Bulletin ◽

10.1016/j.brainresbull.2006.10.003 ◽

2007 ◽

Vol 71 (4) ◽

pp. 337-343 ◽

Cited By ~ 3

Author(s):

Ildikó Wéber ◽

Zita Puskár ◽

Norbert Kozák ◽

Miklós Antal

Keyword(s):

Spinal Cord ◽

Lumbar Spinal Cord ◽

Primary Afferent ◽

Afferent Fibers ◽

Primary Afferent Fibers ◽

Lumbar Spinal

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Substance P Signaling Contributes to Granuloma Formation inTaenia crassicepsInfection, a Murine Model of Cysticercosis

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/597086 ◽

2010 ◽

Vol 2010 ◽

pp. 1-6 ◽

Cited By ~ 13

Author(s):

Armandina Garza ◽

David J. Tweardy ◽

Joel Weinstock ◽

Balaji Viswanathan ◽

Prema Robinson

Keyword(s):

Substance P ◽

Potential Role ◽

Cytokine Production ◽

Taenia Solium ◽

Granuloma Formation ◽

Wild Type ◽

Granulomatous Reaction ◽

Pain Transmission ◽

Neurokinin 1 ◽

The Brain

Cysticercosis is an infection with larval cysts of the cestodeTaenia solium. Through pathways that are incompletely understood, dying parasites initiate a granulomatous reaction that, in the brain, causes seizures. Substance P (SP), a neuropeptide involved in pain-transmission, contributes to inflammation and previously was detected in granulomas associated with deadT. crassicepscysts. To determine if SP contributes to granuloma formation, we measured granuloma-size and levels of IL-1β, TNF-α, and IL-6 within granulomas inT. crassiceps-infected wild type (WT) mice and mice deficient in SP-precursor (SPP) or the SP-receptor (neurokinin 1, NK1). Granuloma volumes of infected SPP- and NK1-knockout mice were reduced by 31 and 36%, respectively, compared to WT mice (P<.05for both) and produced up to 5-fold less IL-1β, TNF-α, and IL-6 protein. Thus, SP signaling contributes to granuloma development and proinflammatory cytokine production inT. crassicepsinfection and suggests a potential role for this mediator in human cystercercosis.

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Response and receptive-field properties of spinomesencephalic tract cells in the cat

Journal of Neurophysiology ◽

10.1152/jn.1986.55.1.76 ◽

1986 ◽

Vol 55 (1) ◽

pp. 76-96 ◽

Cited By ~ 41

Author(s):

R. P. Yezierski ◽

R. H. Schwartz

Keyword(s):

Spinal Cord ◽

Receptive Field ◽

Dynamic Range ◽

Receptive Fields ◽

The Body ◽

Noxious Stimulation ◽

Primary Afferent ◽

Receptive Field Properties ◽

Afferent Fibers ◽

Primary Afferent Fibers

Recordings were made from 90 identified spinomesencephalic tract (SMT) cells in the lumbosacral spinal cord of cats anesthetized with alpha-chloralose and pentobarbital sodium. Recording sites were located in laminae I-VIII. Antidromic stimulation sites were located in different regions of the rostral and caudal midbrain including the periaqueductal gray, midbrain reticular formation, and the deep layers of the superior colliculus. Twelve SMT cells were antidromically activated from more than one midbrain level or from sites in the medial thalamus. The mean conduction velocity for the population of cells sampled was 45.2 +/- 21.4 m/s. Cells were categorized based on their responses to graded intensities of mechanical stimuli and the location of excitatory and/or inhibitory receptive fields. Four major categories of cells were encountered: wide dynamic range (WDR); high threshold (HT); deep/tap; and nonresponsive. WDR and HT cells had excitatory and/or inhibitory receptive fields restricted to the ipsilateral hindlimb or extending to other parts of the body including the tail, forelimbs, and face. Some cells had long afterdischarges following noxious stimulation, whereas others had high rates of background activity that was depressed by nonnoxious and noxious stimuli. Deep/tap cells received convergent input from muscle, joint, or visceral primary afferent fibers. The placement of mechanical lesions at different rostrocaudal levels of the cervical spinal cord provided information related to the spinal trajectory of SMT axons. Six axons were located contralateral to the recording electrode in the ventrolateral/medial or lateral funiculi while two were located in the ventrolateral funiculus of the ipsilateral spinal cord. Stimulation at sites used to antidromically activate SMT cells resulted in the inhibition of background and evoked responses for 22 of 25 cells tested. Inhibitory effects were observed on responses evoked by low/high intensity cutaneous stimuli and by the activation of joint or muscle primary afferent fibers. Based on the response and receptive-field properties of SMT cells it is suggested that the SMT may have an important role in somatosensory mechanisms, particularly those related to nociception.

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Synergistic Enhancement of Glutamate-Mediated Responses by Serotonin and Forskolin in Adult Mouse Spinal Dorsal Horn Neurons

Journal of Neurophysiology ◽

10.1152/jn.00423.2001 ◽

2002 ◽

Vol 87 (2) ◽

pp. 732-739 ◽

Cited By ~ 24

Author(s):

Guo-Du Wang ◽

Min Zhuo

Keyword(s):

Spinal Cord ◽

Nmda Receptors ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Adult Mouse ◽

Dorsal Horn Neurons ◽

Spinal Dorsal ◽

Afferent Fibers ◽

Primary Afferent Fibers ◽

Spinal Dorsal Horn Neurons

Glutamate is the major excitatory amino acid neurotransmitter in the CNS, including the neocortex, hippocampus, and spinal cord. Normal synaptic transmission is mainly mediated by glutamate AMPA and/or kainate receptors. Glutamate N-methyl-d-aspartate (NMDA) receptors are normally inactive and only activated when a sufficient postsynaptic depolarization is induced by the activity. Here we show that in sensory synapses of adult mouse, some synaptic responses (26.3% of a total of 38 experiments) between primary afferent fibers and dorsal horn neurons are almost completely mediated by NMDA receptors. Dorsal root stimulation did not elicit any detectable AMPA/kainate receptor-mediated responses in these synapses. Unlike young spinal cord, serotonin alone did not produce any long-lasting synaptic enhancement in adult spinal dorsal horn neurons. However, co-application of the adenylyl cyclase activator forskolin and serotonin (5-HT) produced long-lasting enhancement, including the recruitment of functional AMPA receptor-mediated responses. Calcium-sensitive, calmodulin-regulated adenylyl cyclases (AC1, AC8) are required for the enhancement. Furthermore the thresholds for generating action potential responses were decreased, and, in many cases, co-application of forskolin and 5-HT led to the generation of action potentials by previously subthreshold stimulation of primary afferent fibers in the presence of the NMDA receptor blocker 2-amino-5-phosphonovaleric acid. Our results suggest that pure NMDA synapses exist on sensory neurons in adult spinal cord and that they may contribute to functional sensory transmission. The synergistic recruitment of functional AMPA responses by 5-HT and forskolin provides a new cellular mechanism for glutamatergic synapses in mammalian spinal cord.

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