Acetaminophen Inhibits Spinal Prostaglandin E2Release after Peripheral Noxious Stimulation

Background Prostaglandin play a pivotal role in spinal nociceptive processing. At therapeutic concentrations, acetaminophen is not a cyclooxygenase inhibitor. inhibitor. Thus, it is antinociceptive without having antiinflammatory or gastrointestinal toxic effects. This study evaluated the role of spinal prostaglandin E2 (PGE2) in antinociception produced by intraperitoneally administered acetaminophen. Methods The PGE2 concentrations in the dorsal horn of the spinal cord were measured after formalin was injected into the hind paw of rats. The effect of antinociceptive doses of acetaminophen (100, 200, and 300 mg/kg given intraperitoneally) on PGE2 levels and flinching behavior was monitored Spinal PGE2 and acetaminophen concentrations were obtained by microdialysis using a probe that was implanted transversely through the dorsal horn of the spinal cord at L4. Furthermore, the effects of acetaminophen on urinary prostaglandin excretion were determined. Results Intraperitoneal administration of acetaminophen resulted in a significant decrease in spinal PGE2 release that was associated with a significant reduction in the flinching behavior in the formalin test Acetaminophen was distributed rapidly into the spinal cord with maximum dialysate concentrations 4560 min after intraperitoneal administration. Urinary excretion of prostanoids (PGE2, PGF2alpha, and 6-keto-PGF1alpha) was not significantly altered after acetaminophen administration. Conclusions The data confirm the importance of PGE2 in spinal nociceptive processing. The results suggest that antinociception after acetaminophen administration is mediated, at least in part, by inhibition of spinal PGE2 release. The mechanism, however, remains unknown. The finding that urinary excretion of prostaglandins was not affected might explain why acetaminophen is antinociceptive but does not compromise renal safety.

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Microglial refinement of spinal cord sensory circuitry regulates normal maturation of dynamic touch.

10.1101/2021.03.22.436389 ◽

2021 ◽

Author(s):

Yajing Xu ◽

Stephanie Koch ◽

Alexander Chamessian ◽

Qianru He ◽

Mayya Sundukova ◽

...

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Normal Development ◽

Physiological Role ◽

Spinal Cord Dorsal Horn ◽

Dynamic Touch ◽

Tactile Sensitivity ◽

Primary Afferent ◽

Spinal Cord Dorsal

In the spinal cord dorsal horn, sensory circuits undergo remarkable postnatal reorganisation, including refinement of primary afferent A-fibres in the superficial layers, accompanied by decreased cutaneous sensitivity. Here we show a physiological role of microglia necessary for normal development of dorsal horn sensory circuits and tactile sensitivity. In the absence of microglial engulfment, superfluous A-fibre projections persist, leading to lifelong hypersensitivity to dynamic touch.

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Multiple Firing Patterns in Deep Dorsal Horn Neurons of the Spinal Cord: Computational Analysis of Mechanisms and Functional Implications

Journal of Neurophysiology ◽

10.1152/jn.00919.2009 ◽

2010 ◽

Vol 104 (4) ◽

pp. 1978-1996 ◽

Cited By ~ 11

Author(s):

Yann Le Franc ◽

Gwendal Le Masson

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Information Transfer ◽

Network Effects ◽

Neuronal Response ◽

Sensory Information ◽

Firing Patterns ◽

Dorsal Horn Neurons ◽

The Impact

Deep dorsal horn relay neurons (dDHNs) of the spinal cord are known to exhibit multiple firing patterns under the control of local metabotropic neuromodulation: tonic firing, plateau potential, and spontaneous oscillations. This work investigates the role of interactions between voltage-gated channels and the occurrence of different firing patterns and then correlates these two phenomena with their functional role in sensory information processing. We designed a conductance-based model using the NEURON software package, which successfully reproduced the classical features of plateau in dDHNs, including a wind-up of the neuronal response after repetitive stimulation. This modeling approach allowed us to systematically test the impact of conductance interactions on the firing patterns. We found that the expression of multiple firing patterns can be reproduced by changes in the balance between two currents (L-type calcium and potassium inward rectifier conductances). By investigating a possible generalization of the firing state switch, we found that the switch can also occur by varying the balance of any hyperpolarizing and depolarizing conductances. This result extends the control of the firing switch to neuromodulators or to network effects such as synaptic inhibition. We observed that the switch between the different firing patterns occurs as a continuous function in the model, revealing a particular intermediate state called the accelerating mode. To characterize the functional effect of a firing switch on information transfer, we used correlation analysis between a model of peripheral nociceptive afference and the dDHN model. The simulation results indicate that the accelerating mode was the optimal firing state for information transfer.

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The original description of central sensitization

10.1093/med/9780198834359.003.0040 ◽

2018 ◽

Author(s):

Sheila Black

Keyword(s):

Amino Acids ◽

Dorsal Horn ◽

Central Sensitization ◽

Excitatory Amino Acids ◽

Formalin Test ◽

Tissue Injury ◽

Original Description ◽

Nociceptive Responses ◽

Landmark Study

The landmark study discussed in this chapter is ‘The contribution of excitatory amino acids to central sensitization and persistent nociception after formalin-induced tissue injury’, published by Coderre and Melzack in 1992. Previous studies in this field implicate a contribution of excitatory amino acids (EAAs), specifically l-glutamate and l-aspartate, to injury-induced sensitization of nociceptive responses in the dorsal horn of the spinal cord. Repetitive stimulation of primary afferent fibres demonstrated that l-glutamate and NMDA can produce ‘wind-up’ of neuronal dorsal horn activity, and this is blocked by application of NMDA antagonists. This study uses the formalin test as a behavioural model to investigate the mechanisms underlying central sensitization and the role of EAAs, NMDA, their receptors, and their antagonists in this process.

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Increasing Isoflurane from 0.9 to 1.1 Minimum Alveolar Concentration Minimally Affects Dorsal Horn Cell Responses to Noxious Stimulation

Anesthesiology ◽

10.1097/00000542-199901000-00027 ◽

1999 ◽

Vol 90 (1) ◽

pp. 208-214 ◽

Cited By ~ 28

Author(s):

Joseph F. Antognini ◽

Earl Carstens

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Minimum Alveolar Concentration ◽

Neuronal Response ◽

Spinal Cord Dorsal Horn ◽

Noxious Stimulus ◽

Lumbar Spinal Cord ◽

Noxious Stimulation ◽

Neuronal Responses ◽

Cell Responses

Background The spinal cord appears to be the site at which isoflurane suppresses movement that occurs in response to a noxious stimulus. In an attempt to localize its site of suppressant action, the authors determined the effect of isoflurane on dorsal horn neuronal responses to supramaximal noxious stimulation at end-tidal concentrations that just permitted and just prevented movement. Methods Rats (n = 14) were anesthetized with isoflurane, and after lumbar laminectomy, the minimum alveolar concentration (MAC) for each rat was determined using a supramaximal mechanical stimulus. In these same rats, after extracellular microelectrode placement in the lumbar spinal cord, dorsal horn neuronal responses to the supramaximal stimulus were determined at the concentrations of isoflurane that bracketed each rat's MAC (0.1% higher and lower than MAC). The MAC of isoflurane was then re-determined. Results Dorsal horn neuronal response was 1,757+/-892 impulses/min at 0.9 MAC and 1,508+/-988 impulses/min at 1.1 MAC, a 14% decrease (P < 0.05). Cell responses varied, with some cells increasing their response at the higher concentration of isoflurane. The MAC of isoflurane was 1.38+/-0.2% before and 1.34+/-0.2% after determination of dorsal horn neuronal responses. Conclusions Isoflurane, at concentrations that bracket MAC, has a variable and minimal depressant effect on dorsal horn cell responses to noxious mechanical stimulation. These data suggest that the major action of isoflurane to suppress movement evoked by a noxious stimulus might occur primarily at a site other than the dorsal horn.

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Role of Calcitonin Gene-Related Peptide in the Sensitization of Dorsal Horn Neurons to Mechanical Stimulation After Intradermal Injection of Capsaicin

Journal of Neurophysiology ◽

10.1152/jn.00086.2004 ◽

2004 ◽

Vol 92 (1) ◽

pp. 320-326 ◽

Cited By ~ 44

Author(s):

Rui-Qing Sun ◽

Nada B. Lawand ◽

Qing Lin ◽

William D. Willis

Keyword(s):

Spinal Cord ◽

Receptive Field ◽

Dorsal Horn ◽

Background Activity ◽

Calcitonin Gene Related Peptide ◽

Intradermal Injection ◽

Dorsal Horn Neurons ◽

Related Peptide ◽

Calcitonin Gene

This study was designed to assess the role of calcitonin gene-related peptide (CGRP) and its receptor in the sensitization of dorsal horn neurons induced by intradermal injection of capsaicin in rats. Extracellular recordings were made from wide dynamic range (WDR) dorsal horn neurons with receptive fields on the hindpaw in the lumbar enlargement of anesthetized rats. The background activity and responses to brushing, pressing, and pinching the skin were assessed. A postsuperfusion or a presuperfusion of CGRP8-37 paradigm was followed. When tested 30 min after capsaicin injection, there was an increase in background activity and responses to brush, press, and pinch applied to the receptive field. Superfusion of CGRP8-37 into the spinal cord at 45 min after capsaicin injection significantly reversed the increased background activity and responses to brush, press, and pinch applied to the receptive field. On the other hand, spinal superfusion of CGRP8-37 prior to capsaicin injection prevented the increased background activity and responses to brush, press, and pinch of WDR neurons that occurred following capsaicin injection in control experiments. A sensitization of spinal dorsal horn neurons could also be induced by superfusion of the spinal cord with CGRP. The effect could be blocked by CGRP8-37 dose-dependently. Collectively, these results suggest that CGRP and its receptors are involved in the spinal cord central sensitization induced by intradermal injection of capsaicin.

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Modulation of dorsal horn neuronal activity by spinal cord stimulation in a rat model of neuropathy: The role of the dorsal funicles

Neurophysiology ◽

10.1007/bf03027696 ◽

1998 ◽

Vol 30 (6) ◽

pp. 424-427 ◽

Cited By ~ 13

Author(s):

V. A. Yakhnista ◽

B. Linderoth ◽

B. A. Meyerson

Keyword(s):

Spinal Cord ◽

Dorsal Horn ◽

Neuronal Activity ◽

Rat Model ◽

Spinal Cord Stimulation

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Neuroligins Facilitate The Development of Bone Cancer Pain via Regulating Synaptic Transmission

10.21203/rs.3.rs-991135/v1 ◽

2021 ◽

Author(s):

Xianqiao Xie ◽

Yang Li ◽

Shanchun Su ◽

Xiaohui Li ◽

Xueqin Xu ◽

...

Keyword(s):

Spinal Cord ◽

Chronic Pain ◽

Cancer Pain ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Bone Cancer ◽

Bone Cancer Pain ◽

Rat Spinal Cord ◽

Spinal Dorsal

Abstract Background The underlying mechanism of chronic pain involves the plasticity in synaptic receptors and neurotransmitters. This study aimed to investigate potential roles of neuroligins (NLs) within the spinal dorsal horn of rats in a newly established bone cancer pain (BCP) model. Methods Using our rat BCP model, we assessed pain hypersensitivity over time. Quantitative real-time polymerase chain reaction and Western blot analysis were performed to investigate NL expression, and NLs were overexpressed in the rat spinal cord using lentiviral vectors. Immunofluorescence staining and whole-cell patch-clamp recordings were deployed to investigate the role of NLs in the development of BCP. Results We observed reduced expression levels of NL1 and NL2, but not NL3, within the rat spinal cord, which were found to be associated with and essential for the development of BCP in our model. Accordingly, NL1 or NL2 overexpression in the spinal cord alleviated mechanical hypersensitivity of rats. Electrophysiological experiments indicated that NL1 and NL2 are involved in BCP via regulating γ-aminobutyric acid-ergic interneuronal synapses and the activity of glutamatergic interneuronal synapses, respectively. Conclusions Our observations unravel the role of NLs in cancer-related chronic pain and further suggest that inhibitory mechanisms are central features of BCP in the spinal dorsal horn. These results provide a new perspective and basis for subsequent studies elucidating the onset and progression of BCP.

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