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

2004 ◽  
Vol 100 (4) ◽  
pp. 905-911 ◽  
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.

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

2007 ◽  
Vol 106 (6) ◽  
pp. 1213-1219 ◽  
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.

Age-dependent Responses to Nerve Injury– induced Mechanical Allodynia

2006 ◽  
Vol 104 (2) ◽  
pp. 344-350 ◽  
Author(s):  
Douglas G. Ririe ◽  
James C. Eisenach
Keyword(s):  
Sciatic Nerve ◽  
Nerve Injury ◽  
Nerve Root ◽  
Spinal Nerve ◽  
Developmental Differences ◽  
Mechanical Stimuli ◽  
Spinal Nerve Root ◽  
Withdrawal Threshold ◽  
Partial Sciatic Nerve Ligation ◽  
Sensitizing Effect

Background Developmental differences in responses to acute and chronic nerve injury have received minimal attention. This study examines developmental differences in behavioral responses to a proximal (closer to the spinal cord) (L5 and L6 spinal nerve root ligation) or to a more distal (closer to peripheral innervation) (partial sciatic nerve ligation) nerve injury in rats paralleling the infant to young adult human. Methods Withdrawal thresholds to von Frey filament testing in the hind paw were determined before and various times after either spinal nerve root ligation or partial sciatic nerve ligation in rats aged 2, 4, and 16 weeks. Control rats of these ages were observed serially without surgery. Times for withdrawal thresholds to mechanical stimuli to return to 80% of that of the hind paw in the control animals were compared among the different ages in the two models. Results Baseline withdrawal thresholds in younger rats were lower (P < 0.05). In the 2-week-old animals, distal injury partial sciatic nerve ligation did not cause a reduction in withdrawal threshold from baseline. This was different from the spinal nerve root ligation group and the older animals in the partial sciatic nerve ligation group. However, when compared with age-matched control animals, both nerve injuries resulted in reduced withdrawal thresholds (P < 0.05). The resolution of hypersensitivity to mechanical stimulation, as measured by return of threshold to 80% of controls, occurred more quickly in 2-week-old than in 4- and 16-week-old animals in both injury models (P < 0.05). Conclusion These data suggest that resolution of sensitization to A-fiber input occurs more rapidly in young animals. In addition, distal injury has less of a sensitizing effect on A-fiber input than proximal injury in the younger animals. The authors speculate that neuroimmune responses, especially at the site of injury, are developmentally regulated and less likely to produce chronic pain when injury occurs at a young age.

scholarly journals Resveratrol Mediates Mechanical Allodynia Through Modulating Inflammatory Response via the TREM2-autophagy Axis in SNI Rat Model

2020 ◽  
Author(s):  
Yaping Wang ◽  
Yu Shi ◽  
Yongquan Huang ◽  
Wei Liu ◽  
Guiyuan Cai ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Inflammatory Response ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Rat Model ◽  
Mechanical Allodynia ◽  
Spinal Dorsal Horn ◽  
Intrathecal Administration ◽  
Spared Nerve Injury ◽  
Spinal Dorsal

Abstract Background Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. Methods A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanism allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, Lentivirus coding TREM2 was intrathecal injected into SNI rats to activate TREM2 and the pain behavior was detected by the Von Frey test. Furthermore, 3-Methyladenine (3-MA, an autophagy inhibitor) was performed to analyze the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, immunofluorescence. Results The TREM2 expression and number of the microglial cell was significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-methyladenine in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. Conclusions Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.

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

2004 ◽  
Vol 100 (3) ◽  
pp. 671-675 ◽  
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.

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

Toxins ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 477
Author(s):  
Seunghui Woo ◽  
Geehoon Chung ◽  
Hyunsu Bae ◽  
Sun Kwang Kim
Keyword(s):  
Neuropathic Pain ◽  
Phospholipase A2 ◽  
Nerve Injury ◽  
Mechanical Allodynia ◽  
Spinal Nerve ◽  
Bee Venom ◽  
Sprague Dawley ◽  
Relieve Pain ◽  
Adrenergic Antagonist ◽  
History Of

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.

scholarly journals Intrathecal IGF2 siRNA injection provides long-lasting anti-allodynic effect in a spared nerve injury rat model of neuropathic pain

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0260887
Author(s):  
Wei-Hung Chan ◽  
Nian-Cih Huang ◽  
Yi-Wen Lin ◽  
Feng-Yen Lin ◽  
Chien-Sung Tsai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Protein Expression ◽  
Nerve Injury ◽  
Quantitative Polymerase Chain Reaction ◽  
Response Duration ◽  
Intrathecal Administration ◽  
Significant Inhibition ◽  
Spared Nerve Injury ◽  
Withdrawal Threshold

Previous studies have shown an increase of insulin-like growth factor-2 (IGF2) in animal models of neuropathic pain. We aimed to examine the hypothesis that reducing the expression of IGF2 using intrathecal IGF2 small-interfering RNA (siRNA) would attenuate the development of neuropathic pain in rats after spared nerve injury (SNI). Male Wistar rats were divided into three groups: sham-operated group, in which surgery was performed to cut the muscles without injuring the nerves; SNI group, in which SNI surgery was performed to sever the nerves; and SNI + siRNA IGF2 group, in which SNI surgery was performed, and IGF2-siRNA was administered intrathecally 1 day after SNI. The rats were assessed for mechanical allodynia and cold allodynia 1 day before surgery (baseline), and at 2, 4, 6, 8, and 10 days after siRNA treatment. The rat spinal cord was collected for quantitative polymerase chain reaction and western blot analysis. Compared with the SNI group, rats that received IGF2 siRNA showed a significantly increased SNI-induced paw-withdrawal threshold to metal filament stimulation from Day 4 to Day 10 after SNI surgery. IGF2 siRNA significantly decreased the response duration from the acetone test from Day 2 to Day 10 following SNI surgery. SNI increased IGF2 mRNA expression on Day 2 and increased IGF2 protein expression on Day 8 and Day 10 in the spinal cord of the SNI rats. However, the above-mentioned effects of IGF2 mRNA and protein expression were significantly inhibited in the SNI + IGF2 siRNA group. We demonstrated that intrathecal administration of IGF2 siRNA provided significant inhibition of SNI-induced neuropathic pain via inhibition of IGF2 expression in the spinal cord. The analgesic effect lasted for 10 days. Further exploration of intrathecal IGF2 siRNA administration as a potential therapeutic strategy for neuropathic pain is warranted.

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 Resveratrol mediates mechanical allodynia through modulating inflammatory response via the TREM2-autophagy axis in SNI rat model

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Yaping Wang ◽  
Yu Shi ◽  
Yongquan Huang ◽  
Wei Liu ◽  
Guiyuan Cai ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Inflammatory Response ◽  
Dorsal Horn ◽  
Nerve Injury ◽  
Rat Model ◽  
Mechanical Allodynia ◽  
Spinal Dorsal Horn ◽  
Intrathecal Administration ◽  
Spared Nerve Injury ◽  
Spinal Dorsal

Abstract Background Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. Methods A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanical allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, lentivirus coding TREM2 was intrathecally injected into SNI rats to activate TREM2, and the pain behavior was detected by the von Frey test. Furthermore, 3-methyladenine (3-MA, an autophagy inhibitor) was applied to study the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, and immunofluorescence. Results The TREM2 expression and number of the microglial cells were significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1β, interleukin-6, and tumor necrosis factor-α in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-MA in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. Conclusions Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.

Intrathecal Morphine Reduces Allodynia after Peripheral Nerve Injury in Rats via  Activation of a Spinal A1 Adenosine Receptor

2005 ◽  
Vol 102 (2) ◽  
pp. 416-420 ◽  
Author(s):  
Yong Zhang ◽  
Dawn R. Conklin ◽  
Xinhui Li ◽  
James C. Eisenach
Keyword(s):  
Peripheral Nerve ◽  
Nerve Injury ◽  
Adenosine Receptor ◽  
Peripheral Nerve Injury ◽  
Intrathecal Morphine ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Male Rats ◽  
A1 Adenosine Receptor ◽  
Withdrawal Threshold

Background The degree to which intrathecally administered morphine can alleviate hypersensitivity in animals after peripheral nerve injury is controversial, and the mechanisms by which morphine works in these circumstances are uncertain. In normal animals, morphine induces adenosine release, and in vitro data suggest that this link is disrupted after peripheral nerve injury. Therefore, using a controlled, blinded study design, the authors tested intrathecal morphine efficacy in rats with peripheral nerve injury and the role of spinal A1 adenosine receptors in the action of morphine. Methods Male rats underwent intrathecal catheter implantation and lumbar spinal nerve ligation, resulting in hypersensitivity to tactile stimulation of the paw. Intrathecal morphine alone or with naloxone or the specific A1 adenosine receptor antagonist, 1,3-dipropyl-8-cyclopentyxanthine (DPCPX), was administered, and withdrawal threshold to von Frey filament application to the hind paw was determined. Results Intrathecal morphine (0.25-30 microg) dose-dependently reversed mechanical hypersensitivity after spinal nerve ligation, with an ED50 of 0.79 microg. The effect of morphine was blocked by intrathecal naloxone. Intrathecal DPCPX alone had no effect on withdrawal threshold after spinal nerve ligation but completely reversed the effect of morphine, with an ID50 of 5.6 microg. Conclusions This study is in accord with two recent reports that support short-term efficacy of intrathecal morphine to reverse hypersensitivity to mechanical stimuli in animal models of neuropathic pain. Despite previous studies demonstrating that morphine releases less adenosine after peripheral nerve injury, the current study suggests that the antihypersensitivity effect of morphine in these conditions is totally reliant on A1 adenosine receptor activation.

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