Suppressive Effects of Bee Venom-Derived Phospholipase A2 on Mechanical Allodynia in a Rat Model of Neuropathic Pain

Bee venom (BV) has a long history of being used in traditional Korean medicine to relieve pain. Here, we investigated the effect of BV-derived phospholipase A2 (bvPLA2), a major component of BV, on peripheral nerve injury-induced neuropathic pain in rats. Spinal nerve ligation (SNL) was performed in Sprague Dawley rats to induce neuropathic pain, and paw withdrawal thresholds were measured using von Frey test. Mechanical allodynia, the representative symptom of neuropathic pain, was manifested following SNL and persisted for several weeks. The repetitive bvPLA2 treatment (0.2 mg/kg/day, i.p.) for two days significantly relieved the SNL-induced mechanical allodynia. The antiallodynic effect of bvPLA2 was blocked by spinal pretreatment with α1-adrenergic antagonist prazosin (30 μg, i.t.) but not with α2-adrenergic antagonist idazoxan (50 μg, i.t.). Also, the spinal application of α1-adrenergic agonist phenylephrine (50 μg, i.t.) reduced mechanical allodynia. These results indicate that bvPLA2 could relieve nerve injury-induced neuropathic mechanical allodynia through the activation of spinal α1-adrenergic receptors.

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Peripheral Nerve Injury Sensitizes the Response to Visceral Distension but Not Its Inhibition by the Antidepressant Milnacipran

Anesthesiology ◽

10.1097/00000542-200403000-00030 ◽

2004 ◽

Vol 100 (3) ◽

pp. 671-675 ◽

Cited By ~ 21

Author(s):

Sang-Wook Shin ◽

James C. Eisenach

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Visceral Pain ◽

Spinal Nerve ◽

Reflex Response ◽

Dependent Manner ◽

Sprague Dawley ◽

Withdrawal Threshold ◽

Sprague Dawley Rats ◽

Lumbar Spinal

Background Manipulations that cause hypersensitivity to visceral stimuli have been shown to also result in hypersensitivity to somatic stimuli coming from convergent dermatomes, but the converse has not been examined. The authors tested whether lumbar spinal nerve ligation in rats, a common model of neuropathic pain that results in hypersensitivity to somatic stimuli, also leads to hypersensitivity to visceral stimuli coming from convergent dermatomes and whether pharmacology of inhibition differed between these two sensory modalities. Methods Female Sprague-Dawley rats were anesthetized, and the left L5 and L6 spinal nerves were ligated. Animals received either intrathecal saline or milnacipran (0.1-3 microg), and withdrawal thresholds to mechanical testing in the left hind paw, using von Frey filaments, and visceral testing, using balloon colorectal distension, were determined. Results Nerve ligation resulted in decreases in threshold to withdrawal to somatic mechanical stimulation (from 13 +/- 1.8 g to 2.7 +/- 0.7 g) and also in decreases in threshold to reflex response to visceral stimulation (from 60 mmHg to 40 mmHg). Intrathecal milnacipran increased withdrawal threshold to somatic stimulation in a dose-dependent manner but failed to alter the response to noxious visceral stimulation. Conclusions Injury of nerves innervating somatic structures enhances nociception from stimulation of viscera with convergent input from nearby dermatomes, suggesting that somatic neuropathic pain could be accompanied by an increased likelihood of visceral pain. Lack of efficacy of the antidepressant milnacipran against visceral stimuli suggests that visceral hypersensitivity may not share the same pharmacology of inhibition as somatic hypersensitivity after nerve injury.

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Suppressive effects of bee venom derived phospholipase A2 on mechanical allodynia in a rat model of neuropathic pain

IBRO Reports ◽

10.1016/j.ibror.2019.07.524 ◽

2019 ◽

Vol 6 ◽

pp. S166

Author(s):

Seunghui Woo ◽

Geehoon Chung ◽

Sun Kwang Kim

Keyword(s):

Neuropathic Pain ◽

Phospholipase A2 ◽

Rat Model ◽

Mechanical Allodynia ◽

Bee Venom

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TNF-α-Mediated RIPK1 Pathway Participates in the Development of Trigeminal Neuropathic Pain in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms23010506 ◽

2022 ◽

Vol 23 (1) ◽

pp. 506

Author(s):

Jo Young Son ◽

Jin Sook Ju ◽

Yu Mi Kim ◽

Dong Kuk Ahn

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Mechanical Allodynia ◽

Inflammatory Responses ◽

Inferior Alveolar Nerve ◽

Sprague Dawley ◽

Sprague Dawley Rats ◽

Tnf Α ◽

Factor Α ◽

Inferior Alveolar Nerve Injury

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) participates in the regulation of cellular stress and inflammatory responses, but its function in neuropathic pain remains poorly understood. This study evaluated the role of RIPK1 in neuropathic pain following inferior alveolar nerve injury. We developed a model using malpositioned dental implants in male Sprague Dawley rats. This model resulted in significant mechanical allodynia and upregulated RIPK1 expression in the trigeminal subnucleus caudalis (TSC). The intracisternal administration of Necrosatin-1 (Nec-1), an RIPK1 inhibitor, blocked the mechanical allodynia produced by inferior alveolar nerve injury The intracisternal administration of recombinant rat tumor necrosis factor-α (rrTNF-α) protein in naive rats produced mechanical allodynia and upregulated RIPK1 expression in the TSC. Moreover, an intracisternal pretreatment with Nec-1 inhibited the mechanical allodynia produced by rrTNF-α protein. Nerve injury caused elevated TNF-α concentration in the TSC and a TNF-α block had anti-allodynic effects, thereby attenuating RIPK1 expression in the TSC. Finally, double immunofluorescence analyses revealed the colocalization of TNF receptor and RIPK1 with astrocytes. Hence, we have identified that astroglial RIPK1, activated by the TNF-α pathway, is a central driver of neuropathic pain and that the TNF-α-mediated RIPK1 pathway is a potential therapeutic target for reducing neuropathic pain following nerve injury.

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Antiallodynic Effects of Systemic and Intrathecal Morphine in the Spared Nerve Injury Model of Neuropathic Pain in Rats

Anesthesiology ◽

10.1097/00000542-200404000-00021 ◽

2004 ◽

Vol 100 (4) ◽

pp. 905-911 ◽

Cited By ~ 45

Author(s):

Chengshui Zhao ◽

Jill M. Tall ◽

Richard A. Meyer ◽

Srinivasa N. Raja

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Mechanical Allodynia ◽

Intrathecal Morphine ◽

Spinal Nerve ◽

Glabrous Skin ◽

Mechanical Stimuli ◽

Spared Nerve Injury ◽

Withdrawal Threshold ◽

Hairy Skin

Background The efficacy of opioids for neuropathic pain remains controversial. The effects of morphine on pain behavior were investigated in two animal models of neuropathic pain: the spared nerve injury (SNI) model and the spinal nerve ligation (SNL) model. Methods Nerve injuries were created in rats either by tight ligation and section of the left tibial and common peroneal nerves (SNI) or by unilateral ligation of L5 and L6 spinal nerves (SNL). Paw withdrawal threshold to mechanical stimuli was measured using the up-down method in the hairy and glabrous skin territories of the sural nerve for SNI rats or in the mid-plantar paw of SNL rats. Results Before SNI, the median paw withdrawal thresholds in hairy and glabrous skin were similar (26 g [25%, 75% quartiles: 26, 26 g]). The paw withdrawal threshold decreased after SNI in both hairy and glabrous skin (P < 0.001). Thirty days after the SNI, the threshold in hairy skin (0.3 g) was significantly lower than in glabrous skin (1.9 g; P < 0.001). In blinded experiments, both subcutaneous and intrathecal morphine (0.1-10 microg) dose-dependently attenuated mechanical allodynia induced by SNI measured in the hairy skin, an effect that was naloxone reversible. The ED50 for the intrathecal morphine was 0.52 microg (95% confidence interval, 0.31-0.90 microg). Morphine (1 microg intrathecal) attenuated SNI-induced mechanical allodynia in glabrous skin with potency similar to that in hairy skin. In SNL rats, morphine (30 microg intrathecal) almost completely reversed the SNL-induced mechanical allodynia. Conclusions (1) SNI-induced mechanical allodynia is characterized by a lower paw withdrawal threshold in hairy versus glabrous skin; (2) systemic and intrathecal morphine reverse SNI-induced mechanical allodynia in a dose-dependent fashion; and (3) intrathecal morphine also reverses SNL-induced mechanical allodynia. These results suggest that intrathecal opioids are likely to be effective in the treatment of neuropathic pain.

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Plasticity-Related PKMζSignaling in the Insular Cortex Is Involved in the Modulation of Neuropathic Pain after Nerve Injury

Neural Plasticity ◽

10.1155/2015/601767 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 9

Author(s):

Jeongsoo Han ◽

Minjee Kwon ◽

Myeounghoon Cha ◽

Motomasa Tanioka ◽

Seong-Karp Hong ◽

...

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Nerve Injury ◽

Neural Plasticity ◽

Mechanical Allodynia ◽

Insular Cortex ◽

Long Term Potentiation ◽

Inhibitory Peptide ◽

Term Potentiation ◽

Potential Applications

The insular cortex (IC) is associated with important functions linked with pain and emotions. According to recent reports, neural plasticity in the brain including the IC can be induced by nerve injury and may contribute to chronic pain. Continuous active kinase, protein kinase Mζ(PKMζ), has been known to maintain the long-term potentiation. This study was conducted to determine the role of PKMζin the IC, which may be involved in the modulation of neuropathic pain. Mechanical allodynia test and immunohistochemistry (IHC) of zif268, an activity-dependent transcription factor required for neuronal plasticity, were performed after nerve injury. Afterζ-pseudosubstrate inhibitory peptide (ZIP, a selective inhibitor of PKMζ) injection, mechanical allodynia test and immunoblotting of PKMζ, phospho-PKMζ(p-PKMζ), and GluR1 and GluR2 were observed. IHC demonstrated that zif268 expression significantly increased in the IC after nerve injury. Mechanical allodynia was significantly decreased by ZIP microinjection into the IC. The analgesic effect lasted for 12 hours. Moreover, the levels of GluR1, GluR2, and p-PKMζwere decreased after ZIP microinjection. These results suggest that peripheral nerve injury induces neural plasticity related to PKMζand that ZIP has potential applications for relieving chronic pain.

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Oral Gabapentin Activates Spinal Cholinergic Circuits to Reduce Hypersensitivity after Peripheral Nerve Injury and Interacts Synergistically with Oral Donepezil

Anesthesiology ◽

10.1097/01.anes.0000267605.40258.98 ◽

2007 ◽

Vol 106 (6) ◽

pp. 1213-1219 ◽

Cited By ~ 45

Author(s):

Ken-ichiro Hayashida ◽

Renée Parker ◽

James C. Eisenach

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Intrathecal Injection ◽

Spinal Nerve ◽

Male Rats ◽

Additive Interaction ◽

Alzheimer Dementia ◽

Routes Of Administration ◽

Withdrawal Threshold ◽

The Brain

Background Gabapentin administration into the brain of mice reduces nerve injury-induced hypersensitivity and is blocked by intrathecal atropine and enhanced by intrathecal neostigmine. The authors tested the relevance of these findings to oral therapy by examining the efficacy of oral gabapentin to reduce hypersensitivity after nerve injury in rats and its interaction with the clinically used cholinesterase inhibitor, donepezil. Methods Male rats with hypersensitivity after spinal nerve ligation received gabapentin orally, intrathecally, and intracerebroventricularly with or without intrathecal atropine, and withdrawal threshold to paw pressure was determined. The effects of oral gabapentin and donepezil alone and in combination on withdrawal threshold were determined in an isobolographic design. Results Gabapentin reduced hypersensitivity to paw pressure by all routes of administration, and was more potent and with a quicker onset after intracerebroventricular than intrathecal injection. Intrathecal atropine reversed the effect of intracerebroventricular and oral gabapentin. Oral gabapentin and donepezil interacted in a strongly synergistic manner, with an observed efficacy at one tenth the predicted dose of an additive interaction. The gabapentin-donepezil combination was reversed by intrathecal atropine. Conclusions Although gabapentin may relieve neuropathic pain by actions at many sites, these results suggest that its actions in the brain to cause spinal cholinergic activation predominate after oral administration. Side effects, particularly nausea, cannot be accurately determined on rats. Nevertheless, oral donepezil is well tolerated by patients in the treatment of Alzheimer dementia, and the current study provides the rationale for clinical study of combination of gabapentin and donepezil to treat neuropathic pain.

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Sortilins in neuropathic pain

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2012.05.028 ◽

2012 ◽

Vol 3 (3) ◽

pp. 183-184

Author(s):

M. Richner ◽

O.J. Bjerrum ◽

Y. De Koninck ◽

A. Nykjaer ◽

C.B. Vaegter

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Mechanical Allodynia ◽

Molecular Mechanisms ◽

Intrathecal Injection ◽

Ion Concentration ◽

Down Regulation

AbstractBackground/aimsThe molecular mechanisms underlying neuropathic pain are incompletely understood, but recent data suggest that down-regulation of the chloride extruding co-transporter KCC2 in spinal cord sensory neurons is critical: Following peripheral nerve injury, activated microglia in the spinal cord release BDNF, which stimulates neuronal TrkB receptors and ultimately results in the reduction of KCC2 levels. Consequently, neuronal intracellular chloride ion concentration increases, impairing GABAA-receptor mediated inhibition. We have previously described how the receptor sortilin modulates neurotrophin signaling by facilitating anterograde transport of Trk receptors. Unpublished data further link SorCS2, another member of the Sortilins family of sorting receptors (sortilin, SorLA and SorCS1–3) to BDNF signaling by regulating presynaptic TrkB trafficking. The purpose of this study is to explore the involvement of Sortilins in neuropathic pain.MethodsWe subjected wild-type (wt), sortilin knockout (Sort1-/-) and SorCS2 knockout (SorCS2-/-) mice to the Spared Nerve Injury (SNI) model of peripheral nerve injury. Mechanical allodynia was measured by von Frey filaments using the up-down-up method and a 3-out-of-5 thresshold.ResultsAs previously described by several groups, wt mice developed significant mechanical allodynia following SNI. Interestingly however, mice lacking sortilin or SorCS2 were fully protected from development of allodynia and did not display KCC2 down-regulation following injury. In addition, a single intrathecal injection of antibodies against sortilin or SorCS2 could delay or rescue mechanical allodynia in wt SNI mice for 2-3 days. Finally, neither sortilin nor SorCS2 deficient mice responded to intrathecal injection of BDNF, in contrast to wt mice which developed transient mechanical allodynia.ConclusionWe hypothesize that sortilin and SorCS2 are involved in neuropathic pain development by regulating TrkB signaling. Alternatively, Sortilins may directly influence the regulation of KCC2 membrane levels following injury. Both hypotheses are currently being investigated by our group.

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