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Pain Feb 2014The gate theory of pain, published by Ronald Melzack and Patrick Wall in Science in 1965, was formulated to provide a mechanism for coding the nociceptive component of... (Review)
Review
The gate theory of pain, published by Ronald Melzack and Patrick Wall in Science in 1965, was formulated to provide a mechanism for coding the nociceptive component of cutaneous sensory input. The theory dealt explicitly with the apparent conflict in the 1960s between the paucity of sensory neurons that responded selectively to intense stimuli and the well-established finding that stimulation of the small fibers in peripheral nerves is required for the stimulus to be described as painful. It incorporated recently discovered mechanisms of presynaptic control of synaptic transmission from large and small sensory afferents, which was suggested to "gate" incoming information depending on the balance between these inputs. Other important features included the convergence of small and large sensory inputs on spinal neurons that transmitted the sensory information to the forebrain as well as the ability of descending control pathways to affect the biasing established by the gate. The clarity of the model and its description gave this article immediate visibility, with numerous attempts made to test its various predictions. Although subsequent experiments and clinical findings have made clear that the model is not correct in detail, the general ideas put forth in the article and the experiments they prompted in both animals and patients have transformed our understanding of pain mechanisms.
Topics: Animals; Ganglia, Spinal; Humans; Neural Inhibition; Neurons, Afferent; Pain; Posterior Horn Cells; Presynaptic Terminals; Sensory Gating
PubMed: 24334188
DOI: 10.1016/j.pain.2013.12.010 -
Neurology(R) Neuroimmunology &... May 2023Spinal cord injury (SCI) disrupts the fine-balanced interaction between the CNS and immune system and can cause maladaptive aberrant immune responses. The study examines...
BACKGROUND AND OBJECTIVES
Spinal cord injury (SCI) disrupts the fine-balanced interaction between the CNS and immune system and can cause maladaptive aberrant immune responses. The study examines emerging autoantibody synthesis after SCI with binding to conformational spinal cord epitopes and surface peptides located on the intact neuronal membrane.
METHODS
This is a prospective longitudinal cohort study conducted in acute care and inpatient rehabilitation centers in conjunction with a neuropathologic case-control study in archival tissue samples ranging from acute injury (baseline) to several months thereafter (follow-up). In the cohort study, serum autoantibody binding was examined in a blinded manner using tissue-based assays (TBAs) and dorsal root ganglia (DRG) neuronal cultures. Groups with traumatic motor complete SCI vs motor incomplete SCI vs isolated vertebral fracture without SCI (controls) were compared. In the neuropathologic study, B cell infiltration and antibody synthesis at the spinal lesion site were examined by comparing SCI with neuropathologically unaltered cord tissue. In addition, the CSF in an individual patient was explored.
RESULTS
Emerging autoantibody binding in both TBA and DRG assessments was restricted to an SCI patient subpopulation only (16%, 9/55 sera) while being absent in vertebral fracture controls (0%, 0/19 sera). Autoantibody binding to the spinal cord characteristically detected the substantia gelatinosa, a less-myelinated region of high synaptic density involved in sensory-motor integration and pain processing. Autoantibody binding was most frequent after motor complete SCI (grade American Spinal Injury Association impairment scale A/B, 22%, 8/37 sera) and was associated with neuropathic pain medication. In conjunction, the neuropathologic study demonstrated lesional spinal infiltration of B cells (CD20, CD79a) in 27% (6/22) of patients with SCI, the presence of plasma cells (CD138) in 9% (2/22). IgG and IgM antibody syntheses colocalized to areas of activated complement (C9neo) deposition. Longitudinal CSF analysis of an additional single patient demonstrated de novo (IgM) intrathecal antibody synthesis emerging with late reopening of the blood-spinal cord barrier.
DISCUSSION
This study provides immunologic, neurobiological, and neuropathologic proof-of-principle for an antibody-mediated autoimmunity response emerging approximately 3 weeks after SCI in a patient subpopulation with a high demand of neuropathic pain medication. Emerging autoimmunity directed against specific spinal cord and neuronal epitopes suggests the existence of paratraumatic CNS autoimmune syndromes.
Topics: Humans; Longitudinal Studies; Cohort Studies; Prospective Studies; Case-Control Studies; Spinal Fractures; Spinal Cord Injuries; Neuralgia; Autoantibodies; Epitopes
PubMed: 37019668
DOI: 10.1212/NXI.0000000000200099 -
The Veterinary Clinics of North... Sep 1988In spite of the research that has been performed, pruritus remains a poorly understood sensation. It is important to remember that the majority of information presented... (Review)
Review
In spite of the research that has been performed, pruritus remains a poorly understood sensation. It is important to remember that the majority of information presented here is derived from observations of human subjects. One can only speculate as to how much of this information can be extrapolated to pruritus in animals. Pruritus is closely intertwined with pain and touch. Pain and pruritus sensations are carried on A delta and C fibers, ascend on the lateral spinothalamic tract, and terminate in various brain centers, including the thalamus and the cortex. The gate control theory of pain and pruritus describes the substantia gelatinosa cells as "swinging gates" to modify peripheral input and result in stimulation of higher centers. Central factors reduce or amplify the perception of these cutaneous sensations. Histamine is the classic mediator of pruritus, although it is still unknown whether a final common mediator of pruritus exists. Numerous other mediators include proteases, peptides, substance P, opiate peptides, prostaglandins, and leukotrienes. These may have pruritic properties directly, or may act as histamine liberators to cause pruritus.
Topics: Animals; Pruritus
PubMed: 3055650
DOI: 10.1016/s0195-5616(88)50101-8 -
Progress in Neurobiology Oct 2018The substantia gelatinosa Rolandi (SGR) was first described about two centuries ago. In the following decades an enormous amount of information has permitted us to... (Review)
Review
The substantia gelatinosa Rolandi (SGR) was first described about two centuries ago. In the following decades an enormous amount of information has permitted us to understand - at least in part - its role in the initial processing of pain and itch. Here, I will first provide a comprehensive picture of the histology, physiology, and neurochemistry of the normal SGR. Then, I will analytically discuss the SGR circuits that have been directly demonstrated or deductively envisaged in the course of the intensive research on this area of the spinal cord, with particular emphasis on the pathways connecting the primary afferent fibers and the intrinsic neurons. The perspective existence of neurochemically-defined sets of primary afferent neurons giving rise to these circuits will be also discussed, with the proposition that a cross-talk between different subsets of peptidergic fibers may be the structural and functional substrate of additional gating mechanisms in SGR. Finally, I highlight the role played by slow acting high molecular weight modulators in these gating mechanisms.
Topics: Animals; History, 19th Century; Humans; Mammals; Nerve Net; Neurochemistry; Spinal Cord; Substantia Gelatinosa
PubMed: 29981393
DOI: 10.1016/j.pneurobio.2018.06.012 -
Molecular Pain 2020Volatile anesthetics suppress noxiously evoked activity in the spinal dorsal horn, which could contribute in part to analgesia, immobility. Modulation of excitatory and...
BACKGROUND
Volatile anesthetics suppress noxiously evoked activity in the spinal dorsal horn, which could contribute in part to analgesia, immobility. Modulation of excitatory and inhibitory synaptic transmission in substantia gelatinosa neurons could lead to the suppression of dorsal horn activity; however, this phenomenon has not yet been investigated fully.
METHODS
In urethane-anesthetized rats, extracellular activity of dorsal horn neurons (action potentials) and excitatory/inhibitory postsynaptic currents in substantia gelatinosa neurons were recorded using extracellular and in vivo patch-clamp techniques, respectively, to assess the spontaneous and the noxious-evoked activity. Sevoflurane or desflurane at concentrations ranging from 0.1 to 2 minimum alveolar concentration was administered by inhalation. Hot- and cold-plate tests were performed to assess nociceptive responses during the inhalation of volatile anesthetics at lower anesthetic doses (0.1–0.5 minimum alveolar concentration).
RESULTS
At anesthetic doses (1 and 2 minimum alveolar concentration), both sevoflurane and desflurane decreased the frequency of action potentials in the dorsal horn and the activities of excitatory postsynaptic currents in substantia gelatinosa neurons during pinch stimulation and decreased the activities of spontaneous and miniature excitatory postsynaptic currents. Inhibition of the frequencies was more prominent than that of amplitudes in spontaneous and miniature excitatory postsynaptic currents at these anesthetic doses. However, at subanesthetic doses (0.1 and 0.2 minimum alveolar concentration), desflurane facilitated action potentials and excitatory postsynaptic currents. Inhibitory postsynaptic currents were inhibited by both anesthetics at anesthetic doses (1 and 2 minimum alveolar concentration). Hot- or cold-plate tests showed hyperalgesic effects of desflurane at subanesthetic doses (0.1 and 0.2 minimum alveolar concentration) and a dose-dependent analgesic effect of sevoflurane.
CONCLUSIONS
Sevoflurane and desflurane at anesthetic doses suppressed dorsal horn activity mainly via inhibition of excitatory postsynaptic currents in substantia gelatinosa neurons, which would contribute to their analgesic properties. Presynaptic mechanisms were likely in excitatory postsynaptic currents inhibition. Desflurane but not sevoflurane may have a hyperalgesic effect at subanesthetic doses.
Topics: Anesthetics; Animals; Desflurane; Male; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Sensory Receptor Cells; Sevoflurane; Spinal Cord; Spinal Cord Dorsal Horn; Substantia Gelatinosa; Synaptic Transmission
PubMed: 32048544
DOI: 10.1177/1744806920903149 -
Journal of Neurophysiology Aug 2006
Centralization, central sensitization and neuropathic pain. Focus on "sciatic chronic constriction injury produces cell-type-specific changes in the electrophysiological properties of rat substantia gelatinosa neurons".
Topics: Animals; Central Nervous System; Electrophysiology; Male; Neurons; Peripheral Nervous System Diseases; Rats; Sciatic Nerve; Substantia Gelatinosa
PubMed: 16835360
DOI: 10.1152/jn.00365.2006 -
International Journal of Molecular... Sep 2021To elucidate why naftopidil increases the frequency of spontaneous synaptic currents in only some substantia gelatinosa (SG) neurons, post-hoc analyses were performed....
To elucidate why naftopidil increases the frequency of spontaneous synaptic currents in only some substantia gelatinosa (SG) neurons, post-hoc analyses were performed. Blind patch-clamp recording was performed using slice preparations of SG neurons from the spinal cords of adult rats. Spontaneous inhibitory and excitatory postsynaptic currents (sIPSCs and sEPSCs, respectively) were recorded. The ratios of the frequency and amplitude of the sIPSCs and sEPSCs following the introduction of naftopidil compared with baseline, and after the application of naftopidil, serotonin (5-HT), and prazosin, compared with noradrenaline (NA) were evaluated. First, the sIPSC analysis indicated that SG neurons reached their full response ratio for NA at 50 μM. Second, they responded to 5-HT (50 μM) with a response ratio similar to that for NA, but prazosin (10 μM) did not change the sEPSCs and sIPSCs. Third, the highest concentration of naftopidil (100 μM) led to two types of response in the SG neurons, which corresponded with the reactions to 5-HT and prazosin. These results indicate that not all neurons were necessarily activated by naftopidil, and that the micturition reflex may be regulated in a sophisticated manner by inhibitory mechanisms in these interneurons.
Topics: Adrenergic alpha-Antagonists; Animals; Excitatory Postsynaptic Potentials; Inhibitory Postsynaptic Potentials; Male; Membrane Potentials; Naphthalenes; Neurons; Norepinephrine; Patch-Clamp Techniques; Piperazines; Prazosin; Rats, Sprague-Dawley; Serotonin; Substantia Gelatinosa; Synaptic Transmission; Rats
PubMed: 34502543
DOI: 10.3390/ijms22179636