scholarly journals Phytochemicals of Cinnamomi Cortex: Cinnamic Acid, but not Cinnamaldehyde, Attenuates Oxaliplatin-Induced Cold and Mechanical Hypersensitivity in Rats

Nutrients ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 432 ◽  
Author(s):  
Hyeon Kyeong Chae ◽  
Woojin Kim ◽  
Sun Kwang Kim
Keyword(s):  
Neuropathic Pain ◽  
Cinnamic Acid ◽  
Mechanical Allodynia ◽  
Dynamic Range ◽  
Spinal Pain ◽  
Analgesic Action ◽  
Mechanical Hypersensitivity ◽  
Pain Transmission ◽  
Cinnamomi Cortex

A chemotherapy drug, oxaliplatin, induces cold and mechanical hypersensitivity, but effective treatments for this neuropathic pain without side effects are still lacking. We previously showed that Cinnamomi Cortex suppresses oxaliplatin-induced pain behaviors in rats. However, it remains unknown which phytochemical of Cinnamomi Cortex plays a key role in that analgesic action. Thus, here we investigated whether and how cinnamic acid or cinnamaldehyde, major components of Cinnamomi Cortex, alleviates cold and mechanical allodynia induced by a single oxaliplatin injection (6 mg/kg, i.p.) in rats. Using an acetone test and the von Frey test for measuring cold and mechanical allodynia, respectively, we found that administration of cinnamic acid, but not cinnamaldehyde, at doses of 10, 20 and 40 mg/kg (i.p.) significantly attenuates the allodynic behaviors in oxaliplatin-injected rats with the strongest effect being observed at 20 mg/kg. Our in vivo extracellular recordings also showed that cinnamic acid (20 mg/kg, i.p.) inhibits the increased activities of spinal wide dynamic range neurons in response to cutaneous mechanical and cold stimuli following the oxaliplatin injection. These results indicate that cinnamic acid has an effective analgesic action against oxaliplatin-induced neuropathic pain through inhibiting spinal pain transmission, suggesting its crucial role in mediating the effect of Cinnamomi Cortex.

scholarly journals Evaluation of the GABAA Receptor Expression and the Effects of Muscimol on the Activity of Wide Dynamic Range Neurons Following Chronic Constriction Injury of the Sciatic Nerve in Rats

2021 ◽  
Author(s):  
Mehdi Sadeghi ◽  
◽  
Homa Manaheji ◽  
Jalal Zaringhalam ◽  
Abbas Haghparast ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Gabaa Receptor ◽  
Mechanical Allodynia ◽  
Chronic Constriction Injury ◽  
Dynamic Range ◽  
Thermal Hyperalgesia ◽  
Receptor Expression ◽  
Wide Dynamic Range ◽  
Wdr Neurons ◽  
Α1 Subunit

Introduction: The modality of γ-aminobutyric acid receptors (GABAA) in control of dorsal horn neuronal excitability and inhibition of sensory information is ambiguous. The aim of the present study was to investigate the expression of GABAA receptor and the effects of its agonist muscimol on wide dynamic range (WDR) neuronal activity in the chronic constriction injury (CCI) model of neuropathic pain. Methods: Adult male Wistar rats weighing 200 to 250 g were used for the induction of CCI neuropathy. 14 days after surgery, muscimol (0.5, 1, and 2 mg/kg i.p.) was injected. Then, the behavioral tests were performed. Thereafter, the animals were sacrificed, and the lumbar segments of the spinal cords were collected for Western blot analysis of the GABAA receptor α1 subunit expression. The electrophysiological properties of WDR neurons were studied by single unit recordings in separate groups on the 14th day after CCI. Results: The outcomes indicated the development of thermal hyperalgesia and mechanical allodynia after neuropathy; nonetheless, the expression of GABAA receptor α1 subunit did not change significantly. Moreover, the evoked responses of the WDR neurons to electrical, mechanical, and thermal stimuli were significantly increased. 14 days after CCI, muscimol administration decreased thermal hyperalgesia, mechanical allodynia, and hyper-responsiveness of the WDR neurons in CCI rats. Conclusion: It confirms that the modulation of the spinal GABAA receptors after nerve injury can offer further insights to design new therapeutic agents in order to reduce the neuropathic pain symptoms.

scholarly journals Conventional and Kilohertz-frequency Spinal Cord Stimulation Produces Intensity- and Frequency-dependent Inhibition of Mechanical Hypersensitivity in a Rat Model of Neuropathic Pain

2013 ◽  
Vol 119 (2) ◽  
pp. 422-432 ◽  
Author(s):  
Ronen Shechter ◽  
Fei Yang ◽  
Qian Xu ◽  
Yong-Kwan Cheong ◽  
Shao-Qiu He ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Spinal Cord Stimulation ◽  
Dynamic Range ◽  
Dorsal Column ◽  
Dependent Manner ◽  
Motor Threshold ◽  
Wide Dynamic Range ◽  
Mechanical Hypersensitivity ◽  
Dorsal Column Stimulation

Abstract Background: Spinal cord stimulation (SCS) is a useful neuromodulatory technique for treatment of certain neuropathic pain conditions. However, the optimal stimulation parameters remain unclear. Methods: In rats after L5 spinal nerve ligation, the authors compared the inhibitory effects on mechanical hypersensitivity from bipolar SCS of different intensities (20, 40, and 80% motor threshold) and frequencies (50, 1 kHz, and 10 kHz). The authors then compared the effects of 1 and 50 Hz dorsal column stimulation at high- and low-stimulus intensities on conduction properties of afferent Aα/β-fibers and spinal wide-dynamic–range neuronal excitability. Results: Three consecutive daily SCS at different frequencies progressively inhibited mechanical hypersensitivity in an intensity-dependent manner. At 80% motor threshold, the ipsilateral paw withdrawal threshold (% preinjury) increased significantly from pre-SCS measures, beginning with the first day of SCS at the frequencies of 1 kHz (50.2 ± 5.7% from 23.9 ± 2.6%, n = 19, mean ± SEM) and 10 kHz (50.8 ± 4.4% from 27.9 ± 2.3%, n = 17), whereas it was significantly increased beginning on the second day in the 50 Hz group (38.9 ± 4.6% from 23.8 ± 2.1%, n = 17). At high intensity, both 1 and 50 Hz dorsal column stimulation reduced Aα/β-compound action potential size recorded at the sciatic nerve, but only 1 kHz stimulation was partially effective at the lower intensity. The number of actions potentials in C-fiber component of wide-dynamic–range neuronal response to windup-inducing stimulation was significantly decreased after 50 Hz (147.4 ± 23.6 from 228.1 ± 39.0, n = 13), but not 1 kHz (n = 15), dorsal column stimulation. Conclusions: Kilohertz SCS attenuated mechanical hypersensitivity in a time course and amplitude that differed from conventional 50 Hz SCS, and may involve different peripheral and spinal segmental mechanisms.

scholarly journals ERK activation in noradrenergic and serotonergic brainstem nuclei in chronic pain upon noxious stimulation and antidepressants treatment

2009 ◽  
Vol 15 (S3) ◽  
pp. 7-8
Author(s):  
G. Borges ◽  
E. Berrocoso ◽  
A. Ortega-Alvaro ◽  
J. A. Micó ◽  
F. L. Neto
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Chronic Constriction Injury ◽  
Noxious Stimulation ◽  
Analgesic Action ◽  
Chronic Neuropathic Pain ◽  
Erk Activation ◽  
Pain Transmission ◽  
Extracellular Signal ◽  
Brainstem Nuclei

AbstractChronic neuropathic pain is a pathology that affects thousands of people worldwide. Antidepressants have been prescribed for the treatment of this sort of pain but the mechanisms underlying their analgesic action remain unknown. Extracellular-signal regulated kinases (ERKs) are being implicated in pain transmission and modulation as well as in the pathophysiology of depression. In order to clarify some of the mechanisms which might be related to the analgesic effect of antidepressants, we started by evaluating possible changes in the pattern of activation of ERKs in rats with chronic constriction injury (CCI), an experimental model of chronic

Receptor Subtype Mediating the Adrenergic Sensitivity of Pain Behavior and Ectopic Discharges in Neuropathic Lewis Rats

1999 ◽  
Vol 81 (5) ◽  
pp. 2226-2233 ◽  
Author(s):  
Doo Hyun Lee ◽  
Xianzeng Liu ◽  
Hyun Taek Kim ◽  
Kyungsoon Chung ◽  
Jin Mo Chung
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Root ◽  
Mechanical Allodynia ◽  
Pain Behavior ◽  
Receptor Subtype ◽  
Systemic Injection ◽  
Lewis Rats ◽  
Ectopic Discharges

Receptor subtype mediating the adrenergic sensitivity of pain behavior and ectopic discharges in neuropathic Lewis rats. We attempted to identify the subtype of α-adrenergic receptor (α-AR) that is responsible for the sympathetic (adrenergic) dependency of neuropathic pain in the segmental spinal injury (SSI) model in the Lewis strain of rat. This model was chosen because our previous study showed that pain behaviors in this condition are particularly sensitive to systemic injection of phentolamine (PTL), a general α-AR blocker. We examined the effects of specific α1- and α2-AR blockers on 1) behavioral signs of mechanical allodynia, 2) ectopic discharges recorded in the in vivo condition, and 3) ectopic discharges recorded in an in vitro setup. One week after tight ligation of the L5 and L6 spinal nerves, mechanical thresholds of the paw for foot withdrawals were drastically lowered; we interpreted this change as a sign of mechanical allodynia. Signs of mechanical allodynia were significantly relieved by a systemic injection of PTL (a mixed α1- and α2-AR antagonist) or terazosin (TRZ, an α1-AR antagonist) but not by various α2-AR antagonists (idazoxan, rauwolscine, or yohimbine), suggesting that the α1-AR is in part the mediator of the signs of mechanical allodynia. Ongoing ectopic discharges were recorded from injured afferents in fascicles of the L5 dorsal root of the neuropathic rat with an in vivo recording setup. Ongoing discharge rate was significantly reduced after intraperitoneal injection of PTL or TRZ but not by idazoxan. In addition, by using an in vitro recording setup, spontaneous activity was recorded from teased dorsal root fibers in a segment in which the spinal nerve was previously ligated. Application of epinephrine to the perfusion bath enhanced ongoing discharges. This evoked activity was blocked by pretreatment with TRZ but not with idazoxan. This study demonstrated that both behavioral signs of mechanical allodynia and ectopic discharges of injured afferents in the Lewis neuropathic rat are in part mediated by mechanisms involving α1-ARs. These results suggest that the sympathetic dependency of neuropathic pain in the Lewis strain of the rat is mediated by the α1 subtype of AR.

scholarly journals A Combined Water Extract of Frankincense and Myrrh Alleviates Neuropathic Pain in Mice via Modulation of TRPV1

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Danyou Hu ◽  
Changming Wang ◽  
Fengxian Li ◽  
Shulan Su ◽  
Niuniu Yang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Mouse Model ◽  
Mechanical Allodynia ◽  
Transient Receptor Potential ◽  
Water Extract ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Nociceptive Response ◽  
Thermal Hypersensitivity

Frankincense and myrrh are widely used in clinics as a pair of herbs to obtain a synergistic effect for relieving pain. To illuminate the analgesia mechanism of frankincense and myrrh, we assessed its effect in a neuropathic pain mouse model. Transient receptor potential vanilloid 1 (TRPV1) plays a crucial role in neuropathic pain and influences the plasticity of neuronal connectivity. We hypothesized that the water extraction of frankincense and myrrh (WFM) exerted its analgesia effect by modulating the neuronal function of TRPV1. In our study, WFM was verified by UHPLC-TQ/MS assay. In vivo study showed that nociceptive response in mouse by heat and capsaicin induced were relieved by WFM treatment. Furthermore, thermal hypersensitivity and mechanical allodynia were also alleviated by WFM treatment in a chronic constriction injury (CCI) mouse model. CCI resulted in increased TRPV1 expression at both the mRNA and protein levels in predominantly small-to-medium neurons. However, after WFM treatment, TRPV1 expression was reverted in real-time PCR, Western blot, and immunofluorescence experiments. Calcium response to capsaicin was also decreased in cultured DRG neurons from CCI model mouse after WFM treatment. In conclusion, WFM alleviated CCI-induced mechanical allodynia and thermal hypersensitivity via modulating TRPV1.

scholarly journals Zerumbone Ameliorates Neuropathic Pain Symptoms via Cannabinoid and PPAR Receptors Using In Vivo and In Silico Models

Molecules ◽  
2021 ◽  
Vol 26 (13) ◽  
pp. 3849
Author(s):  
Jasmine Siew Min Chia ◽  
Ahmad Akira Omar Farouk ◽  
Tengku Azam Shah Tengku Mohamad ◽  
Mohd Roslan Sulaiman ◽  
Hanis Zakaria ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Mechanical Allodynia ◽  
Thermal Hyperalgesia ◽  
Docking Studies ◽  
Peroxisome Proliferator ◽  
Chronic Pain Condition ◽  
Peroxisome Proliferator Activated Receptors ◽  
Pain Symptoms ◽  
In Silico Models

Neuropathic pain is a chronic pain condition persisting past the presence of any noxious stimulus or inflammation. Zerumbone, of the Zingiber zerumbet ginger plant, has exhibited anti-allodynic and antihyperalgesic effects in a neuropathic pain animal model, amongst other pharmacological properties. This study was conducted to further elucidate the mechanisms underlying zerumbone’s antineuropathic actions. Research on therapeutic agents involving cannabinoid (CB) and peroxisome proliferator-activated receptors (PPARs) is rising. These receptor systems have shown importance in causing a synergistic effect in suppressing nociceptive processing. Behavioural responses were assessed using the von Frey filament test (mechanical allodynia) and Hargreaves plantar test (thermal hyperalgesia), in chronic constriction injury (CCI) neuropathic pain mice. Antagonists SR141716 (CB1 receptor), SR144528 (CB2 receptor), GW6471 (PPARα receptor) and GW9662 (PPARγ receptor) were pre-administered before the zerumbone treatment. Our findings indicated the involvement of CB1, PPARα and PPARγ in zerumbone’s action against mechanical allodynia, whereas only CB1 and PPARα were involved against thermal hyperalgesia. Molecular docking studies also suggest that zerumbone has a comparable and favourable binding affinity against the respective agonist on the CB and PPAR receptors studied. This finding will contribute to advance our knowledge on zerumbone and its significance in treating neuropathic pain.

scholarly journals Evaluation of the GABAA Receptor Expression and the Effects of Muscimol on the Activity of Wide Dynamic Range Neurons Following Chronic Constriction Injury of the Sciatic Nerve in Rats

2021 ◽  
Author(s):  
Mehdi Sadeghi ◽  
Keyword(s):  
Neuropathic Pain ◽  
Gabaa Receptor ◽  
Mechanical Allodynia ◽  
Chronic Constriction Injury ◽  
Dynamic Range ◽  
Thermal Hyperalgesia ◽  
Receptor Expression ◽  
Wide Dynamic Range ◽  
Wdr Neurons ◽  
Α1 Subunit

Introduction: The modality of γ-aminobutyric acid receptors (GABAA) in control of dorsal horn neuronal excitability and inhibition of sensory information is ambiguous. The aim of the present study was to investigate the expression of GABAA receptor and the effects of its agonist muscimol on wide dynamic range (WDR) neuronal activity in the chronic constriction injury (CCI) model of neuropathic pain. Methods: Adult male Wistar rats weighing 200 to 250 g were used for the induction of CCI neuropathy. 14 days after surgery, muscimol (0.5, 1, and 2 mg/kg i.p.) was injected. Then, the behavioral tests were performed. Thereafter, the animals were sacrificed, and the lumbar segments of the spinal cords were collected for Western blot analysis of the GABAA receptor α1 subunit expression. The electrophysiological properties of WDR neurons were studied by single unit recordings in separate groups on the 14th day after CCI. Results: The outcomes indicated the development of thermal hyperalgesia and mechanical allodynia after neuropathy; nonetheless, the expression of GABAA receptor α1 subunit did not change significantly. Moreover, the evoked responses of the WDR neurons to electrical, mechanical, and thermal stimuli were significantly increased. 14 days after CCI, muscimol administration decreased thermal hyperalgesia, mechanical allodynia, and hyper-responsiveness of the WDR neurons in CCI rats. Conclusion: It confirms that the modulation of the spinal GABAA receptors after nerve injury can offer further insights to design new therapeutic agents in order to reduce the neuropathic pain symptoms.

scholarly journals The Antiallodynic Action of Pregabalin May Depend on the Suppression of Spinal Neuronal Hyperexcitability in Rats with Spared Nerve Injury

2014 ◽  
Vol 19 (4) ◽  
pp. 205-211 ◽  
Author(s):  
Lei Ding ◽  
Jie Cai ◽  
Xiang-Yang Guo ◽  
Xiu-Li Meng ◽  
Guo-Gang Xing
Keyword(s):  
Neuropathic Pain ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Dynamic Range ◽  
Inhibitory Effect ◽  
Electrophysiological Recording ◽  
Spared Nerve Injury ◽  
Withdrawal Threshold ◽  
Wdr Neurons

BACKGROUND: Pregabalin (PGB) is a novel antiepileptic drug and is also used as a first-line medication for the treatment of neuropathic pain. However, the mechanisms of its analgesic effects remain largely unknown.OBJECTIVES: To elucidate the mechanisms underlying the antiallodynic action of PGB in rats with neuropathic pain.METHODS: In a rat model of neuropathic pain induced by spared nerve injury, mechanical allodynia, as a behavioural sign of neuropathic pain, was assessed by measuring 50% paw withdrawal threshold with von Frey filaments. Activities of dorsal horn wide dynamic range (WDR) neurons were examined by extracellular electrophysiological recording in vivo.RESULTS: Spinal administration of PGB exerted a significant antiallodynic effect and a prominent inhibitory effect on the hypersensitivity of dorsal horn WDR neurons in rats with spared nerve injury.CONCLUSION: The antiallodynic action of PGB is likely dependent on the suppression of WDR neuron hyperexcitability in rats with neuropathic pain.

scholarly journals Involvement of ASIC1a channels in the spinal processing of pain information by deep projection neurons

2021 ◽  
Author(s):  
Magda Chafai ◽  
Ariane Delrocq ◽  
Perrine Inquimbert ◽  
Ludivine Pidoux ◽  
Kevin Delanoe ◽  
...  
Keyword(s):  
Dynamic Range ◽  
Ex Vivo ◽  
Computational Modelling ◽  
Functional Expression ◽  
Spinal Pain ◽  
Projection Neurons ◽  
Positive Contribution ◽  
Calcium Dependent ◽  
Wdr Neurons

Dorsal horn of the spinal cord is an important crossroad of pain neuraxis, especially for the neuronal plasticity mechanisms that can lead to chronic pain states. Windup is a well-known spinal pain facilitation process initially described several decades ago, but which exact mechanism is still not fully understood. Here, we combine both ex vivo and in vivo electrophysiological recordings of spinal neurons with computational modelling to demonstrate a role for ASIC1a-containing channels in the windup process. Spinal application of the ASIC1a inhibitory venom peptides mambalgin-1 and psalmotoxin-1 (PcTx1) significantly reduces the ability of deep wide dynamic range (WDR) neurons to develop windup in vivo. All deep WDR-like neurons recorded from spinal slices exhibit an ASIC current with biophysical and pharmacological characteristics consistent with functional expression of ASIC1a/ASIC2 heteromeric channels. A computational model of WDR neuron supplemented with heteromeric ASIC1a/ASIC2 channel parameters accurately reproduces the experimental data, further supporting a positive contribution of these channels to windup. It also predicts a calcium-dependent windup decrease for elevated ASIC conductances, a phenomenon that was experimentally validated using either a combination of calcium-activated potassium channel inhibitory peptides (apamin and iberiotoxin), or the Texas coral snake ASIC-activating toxin (MitTx). This study demonstrates a possible dual contribution to windup of calcium permeable ASIC1a/ASIC2 channels in deep laminae projecting neurons, promoting it upon moderate channel activity, but ultimately leading to calcium-dependent windup inhibition associated to potassium channels when activity increases.

scholarly journals Studies on CRMP2 SUMOylation-deficient transgenic mice identify sex-specific NaV1.7 regulation in the pathogenesis of chronic neuropathic pain

2020 ◽  
Author(s):  
Aubin Moutal ◽  
Song Cai ◽  
Jie Yu ◽  
Harrison J. Stratton ◽  
Aude Chefdeville ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Mechanical Allodynia ◽  
Visceral Pain ◽  
Thermal Sensitivity ◽  
Neuronal Firing ◽  
Membrane Localization ◽  
Mediator Protein ◽  
And Function ◽  
Druggable Targets

AbstractThe sodium channel NaV1.7 is a master regulator of nociceptive neuronal firing. Mutations in this channel can result in painful conditions as well as produce insensitivity to pain. Despite being recognized as a “poster child” for nociceptive signaling and human pain, targeting NaV1.7 has not yet produced a clinical drug. Recent work has illuminated the NaV1.7 interactome, offering insights into the regulation of these channels and identifying potentially new druggable targets. Amongst the regulators of NaV1.7 is the cytosolic collapsin response mediator protein 2 (CRMP2). CRMP2, modified at Lysine 374 (K374) by addition of a small ubiquitin-like modifier (SUMO), bound NaV1.7 to regulate its membrane localization and function. Corollary to this, preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in rats with neuropathic pain. Notably, loss of CRMP2 SUMOylation did not compromise other innate functions of CRMP2. To further elucidate the in vivo role of CRMP2 SUMOylation in pain, we generated CRMP2 K374A knock-in (CRMP2K374A/K374A) mice in which Lys374 was replaced with Ala. CRMP2K374A/K374A mice had reduced NaV1.7 membrane localization and function in female, but not male, sensory neurons. Behavioral appraisal of CRMP2K374A/K374A mice demonstrated no changes in depressive or repetitive, compulsive-like behaviors, and a decrease in noxious thermal sensitivity. No changes were observed in CRMP2K374A/K374A mice to inflammatory, acute, or visceral pain. In contrast, in a neuropathic model, CRMP2K374A/K374A mice failed to develop persistent mechanical allodynia. Our study suggests that CRMP2 SUMOylation-dependent control of peripheral NaV1.7 is a hallmark of chronic, but not physiological, neuropathic pain.

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