Cannabinoid CB2 receptor activation inhibits mechanically evoked responses of wide dynamic range dorsal horn neurons in naïve rats and in rat models of inflammatory and neuropathic pain

2004 ◽  
Vol 20 (9) ◽  
pp. 2311-2320 ◽  
Author(s):  
Steven J. R. Elmes ◽  
Maulik D. Jhaveri ◽  
Darren Smart ◽  
David A. Kendall ◽  
Victoria Chapman
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Dynamic Range ◽  
Receptor Activation ◽  
Evoked Responses ◽  
Cb2 Receptor ◽  
Wide Dynamic Range ◽  
Rat Models ◽  
Dorsal Horn Neurons

scholarly journals Characterization and pharmacological modulation of noci-responsive deep dorsal horn neurons across diverse rat models of pathological pain

2018 ◽  
Vol 120 (4) ◽  
pp. 1893-1905 ◽  
Author(s):  
Steve McGaraughty ◽  
Katharine L. Chu ◽  
Jun Xu
Keyword(s):  
Dorsal Horn ◽  
High Intensity ◽  
Dynamic Range ◽  
Spontaneous Firing ◽  
Wide Dynamic Range ◽  
Experimental Conditions ◽  
Rat Models ◽  
Dorsal Horn Neurons ◽  
Pathological Pain ◽  
Wdr Neurons

This overview compares the activity of wide dynamic range (WDR) and nociceptive specific (NS) neurons located in the deep dorsal horn across different rat models of pathological pain and following modulation by diverse pharmacology. The data were collected by our group under the same experimental conditions over numerous studies to facilitate comparison. Spontaneous firing of WDR neurons was significantly elevated (>3.7 Hz) in models of neuropathic, inflammation, and osteoarthritic pain compared with naive animals (1.9 Hz) but was very low (<0.5 Hz) and remained unchanged in NS neurons. WDR responses to low-intensity mechanical stimulation were elevated in neuropathic and inflammation models. WDR responses to high-intensity stimuli were enhanced in inflammatory (heat) and osteoarthritis (mechanical) models. NS responses to high-intensity stimulation did not change relative to control in any model examined. Several therapeutic agents reduced both evoked and spontaneous firing of WDR neurons (e.g., TRPV1, TRPV3, Nav1.7, Nav1.8, P2X7, P2X3, H3), other targets affected neither evoked nor spontaneous firing of WDR neurons (e.g., H4, TRPM8, KCNQ2/3), and some only modulated evoked (e.g, ASIC1a, Cav3.2) whereas others decreased evoked but affected spontaneous activity only in specific models (e.g., TRPA1, CB2). Spontaneous firing of WDR neurons was not altered by any peripherally restricted compound or by direct administration of compounds to peripheral sites, although the same compounds decreased evoked activity. Compounds acting centrally were effective against this endpoint. The diversity of incoming/modulating inputs to the deep dorsal horn positions this group of neurons as an important intersection within the pain system to validate novel therapeutics. NEW & NOTEWORTHY Data from multiple individual experiments were combined to show firing properties of wide dynamic range and nociceptive specific spinal dorsal horn neurons across varied pathological pain models. This high-powered analysis describes the sensitization following different forms of injury. Effects of diverse pharmacology on these neurons is also summarized from published and unpublished data all recorded under the same conditions to facilitate comparison. This comprehensive overview describes the function and utility of these neurons.

scholarly journals Hyperalgesia and sensitization of dorsal horn neurons following activation of NK-1 receptors in the rostral ventromedial medulla

2017 ◽  
Vol 118 (5) ◽  
pp. 2727-2744 ◽  
Author(s):  
Sergey G. Khasabov ◽  
Patrick Malecha ◽  
Joseph Noack ◽  
Janneta Tabakov ◽  
Glenn J. Giesler ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Horn ◽  
Dynamic Range ◽  
Receptor Activation ◽  
Rostral Ventromedial Medulla ◽  
Dorsal Horn Neurons ◽  
Descending Modulation ◽  
Ventromedial Medulla ◽  
Neurokinin 1 ◽  
Wdr Neurons

Neurons in the rostral ventromedial medulla (RVM) project to the spinal cord and are involved in descending modulation of pain. Several studies have shown that activation of neurokinin-1 (NK-1) receptors in the RVM produces hyperalgesia, although the underlying mechanisms are not clear. In parallel studies, we compared behavioral measures of hyperalgesia to electrophysiological responses of nociceptive dorsal horn neurons produced by activation of NK-1 receptors in the RVM. Injection of the selective NK-1 receptor agonist Sar9,Met(O2)11-substance P (SSP) into the RVM produced dose-dependent mechanical and heat hyperalgesia that was blocked by coadministration of the selective NK-1 receptor antagonist L-733,060. In electrophysiological studies, responses evoked by mechanical and heat stimuli were obtained from identified high-threshold (HT) and wide dynamic range (WDR) neurons. Injection of SSP into the RVM enhanced responses of WDR neurons, including identified neurons that project to the parabrachial area, to mechanical and heat stimuli. Since intraplantar injection of capsaicin produces robust hyperalgesia and sensitization of nociceptive spinal neurons, we examined whether this sensitization was dependent on NK-1 receptors in the RVM. Pretreatment with L-733,060 into the RVM blocked the sensitization of dorsal horn neurons produced by capsaicin. c-Fos labeling was used to determine the spatial distribution of dorsal horn neurons that were sensitized by NK-1 receptor activation in the RVM. Consistent with our electrophysiological results, administration of SSP into the RVM increased pinch-evoked c-Fos expression in the dorsal horn. It is suggested that targeting this descending pathway may be effective in reducing persistent pain. NEW & NOTEWORTHY It is known that activation of neurokinin-1 (NK-1) receptors in the rostral ventromedial medulla (RVM), a main output area for descending modulation of pain, produces hyperalgesia. Here we show that activation of NK-1 receptors produces hyperalgesia by sensitizing nociceptive dorsal horn neurons. Targeting this pathway at its origin or in the spinal cord may be an effective approach for pain management.

scholarly journals Spinal neuronal excitability and neuroinflammation in a model of chemotherapeutic neuropathic pain: targeting the resolution pathways

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Pongsatorn Meesawatsom ◽  
Gareth Hathway ◽  
Andrew Bennett ◽  
Dumitru Constantin-Teodosiu ◽  
Victoria Chapman
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Microarray Analysis ◽  
Dynamic Range ◽  
Evoked Responses ◽  
Sprague Dawley ◽  
Resolvin D1 ◽  
Post Discharge ◽  
Critical Feature ◽  
Anti Inflammatory

Abstract Background Neuroinflammation is a critical feature of sensitisation of spinal nociceptive processing in chronic pain states. We hypothesised that the resolvin pathways, a unique endogenous control system, may ameliorate aberrant spinal processing of somatosensory inputs associated with chemotherapy-induced neuropathic pain (CINP). Method The paclitaxel (PCX) model of CINP was established in male Sprague-Dawley rats and compared to control rats (n = 23 and 22, respectively). Behavioural pain responses were measured, and either single unit electrophysiological recordings of dorsal horn wide dynamic range (WDR) neurones were performed, or mRNA microarray analysis of the dorsal horn of the spinal cord was undertaken. Results PCX rats exhibited significant changes in behavioural responses to mechanical and cold stimuli. A higher proportion of WDR neurones in PCX rats were polymodal (generating post-discharge following a non-noxious mechanical stimulus, responding to non-noxious cold and exhibiting spontaneous activity) compared to control (p < 0.05). Microarray analysis revealed changes in proinflammatory pathways (Tlr, Tnfrsf1a, Nlrp1a, Cxcr1, Cxcr5, Ccr1, Cx3cr1) and anti-inflammatory lipid resolvin pathways (Alox5ap, Cyp2j4 and Ptgr1) compared to control (p < 0.05). Ingenuity pathway analysis predicted changes in glutamatergic and astrocyte signaling in the PCX group. Activation of the resolvin system via the spinal administration of aspirin-triggered resolvin D1 (AT-RvD1) markedly inhibited (73 ± 7% inhibition) normally non-noxious mechanically (8 g) evoked responses of WDR neurones only in PCX rats, whilst leaving responses to noxious mechanically induced stimuli intact. Inhibitory effects of AT-RvD1were comparable in magnitude to spinal morphine (84 ± 4% inhibition). Conclusion The PCX model of CINP was associated with mechanical allodynia, altered neuronal responses and dysregulation of pro- and anti-inflammatory signalling in the spinal dorsal horn. The resolvin AT-RvD1 selectively inhibited low weight mechanical-evoked responses of WDR neurones in PCX rats, but not in controls. Our data support the targeting of spinal neuroinflammation via the activation of the resolvin system as a new therapeutic approach for CINP.

Intracisternal injection of palmitoylethanolamide inhibits the peripheral nociceptive evoked responses of dorsal horn wide dynamic range neurons

2014 ◽  
Vol 122 (3) ◽  
pp. 369-374 ◽  
Author(s):  
Abimael González-Hernández ◽  
Guadalupe Martínez-Lorenzana ◽  
Javier Rodríguez-Jiménez ◽  
Gerardo Rojas-Piloni ◽  
Miguel Condés-Lara
Keyword(s):  
Dorsal Horn ◽  
Dynamic Range ◽  
Evoked Responses ◽  
Wide Dynamic Range ◽  
Intracisternal Injection ◽  
Wide Dynamic Range Neurons

Selective Cannabinoid CB1 Receptor Activation Inhibits Spinal Nociceptive Transmission In Vivo

2001 ◽  
Vol 86 (6) ◽  
pp. 3061-3064 ◽  
Author(s):  
Sara Kelly ◽  
Victoria Chapman
Keyword(s):  
Dorsal Horn ◽  
Receptor Activation ◽  
Evoked Responses ◽  
Somatosensory Processing ◽  
Sprague Dawley ◽  
Nociceptive Transmission ◽  
Dorsal Horn Neurons ◽  
Anesthetized Rats ◽  
C Fiber

Cannabinoid1 (CB1) receptors are located at CNS sites, including the spinal cord, involved in somatosensory processing. Analgesia is one of the tetrad of behaviors associated with cannabinoid agonists. Here, effects of a potent cannabinoid CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA) on evoked responses of dorsal horn neurons in anesthetized rats were investigated. Extracellular recordings of convergent dorsal horn neurons were made in halothane anesthetized Sprague-Dawley rats ( n = 16). Effects of spinal application of ACEA on electrically evoked responses of dorsal horn neurons were studied. Mean maximal effects of 0.5, 5, 50, and 500 ng/50 μl ACEA on the C-fiber-mediated postdischarge response were 79 ± 6, 62 ± 10, and 54 ± 7% ( P < 0.01), 45 ± 6% ( P < 0.01), of control, respectively. ACEA (500 ng/50 μl) also reduced the C-fiber-evoked nonpotentiated responses of neurons (59 ± 9% of control, P < 0.05) and Aδ-fiber-evoked responses of neurons (68 ± 10% of control, P < 0.01). Minor effects of ACEA on Aβ-fiber-evoked responses were observed. Spinal pre-administration of the selective CB1 receptor antagonist SR141716A (0.01 μg/50 μl) significantly reduced effects of ACEA (500 ng/50 μl) on postdischarge responses of dorsal horn neurons. This study demonstrates that spinal CB1 receptors modulate the transmission of C- and Aδ-fiber-evoked responses in anesthetized rats; this may reflect pre- and/or postsynaptic effects of cannabinoids on nociceptive transmission. CB1 receptors inhibit synaptic release of glutamate in rat dorsolateral striatum, a similar mechanism of action may underlie the effects of ACEA on noxious evoked responses of spinal neurons reported here.

Wide-dynamic-range dorsal horn neurons participate in the encoding process by which monkeys perceive the intensity of noxious heat stimuli

1986 ◽  
Vol 374 (2) ◽  
pp. 385-388 ◽  
Author(s):  
William Maixner ◽  
Ronald Dubner ◽  
M. Catherine Bushnell ◽  
Daniel R. Kenshalo ◽  
Jean-Louis Oliveras
Keyword(s):  
Dorsal Horn ◽  
Dynamic Range ◽  
Wide Dynamic Range ◽  
Noxious Heat ◽  
Dorsal Horn Neurons

Opioids modulate N-methyl-D-aspartic acid (NMDA)-evoked responses of trigeminothalamic neurons

1996 ◽  
Vol 76 (3) ◽  
pp. 2093-2096 ◽  
Author(s):  
X. M. Wang ◽  
S. S. Mokha
Keyword(s):  
Nmda Receptor ◽  
Dorsal Horn ◽  
Aspartic Acid ◽  
Opioid Receptor ◽  
Receptor Agonist ◽  
Receptor Activation ◽  
Evoked Responses ◽  
Nociceptive Neurons ◽  
Nociceptive Transmission ◽  
Opioid Receptor Agonist

1. The present study investigated opioid-mediated modulation of N-methyl-D-aspartic acid (NMDA)-evoked responses of trigeminothalamic neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in rats anesthetized with urethane. 2. Microiontophoretic application of NMDA activated 18/19 trigeminothalamic neurons. Administration of [D-Ala2, N-Me-Phe4,Gly5-ol]-Enkephalin, a selective mu-opioid receptor agonist, reduced the NMDA-evoked responses in 77% of trigeminothalamic neurons. [D-Pen2,5]-Enkephalin, a selective delta-opioid receptor agonist, produced inhibition of NMDA-evoked responses in 36% of neurons. 3. We suggest that 1) NMDA-receptor activation excites trigeminothalamic nociceptive neurons and may, therefore, mediate nociceptive transmission in the medullary dorsal horn; and 2) the predominantly inhibitory modulation of NMDA-receptor-mediated responses of nociceptive trigeminothalamic neurons by activation of mu- and delta-opioid receptors may provide a neural mechanism for the antinociceptive actions of opioids.

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