Morphine-induced Spinal Release of Adenosine Is Reduced in Neuropathic Rats

2001 ◽  
Vol 95 (6) ◽  
pp. 1455-1459 ◽  
Author(s):  
Andreas Sandner-Kiesling ◽  
Xinhui Li ◽  
James C. Eisenach
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Lumbar Spinal Cord ◽  
Sprague Dawley ◽  
Dorsal Spinal Cord ◽  
Adenosine Release ◽  
Sprague Dawley Rats ◽  
Lumbar Spinal

Background Spinally administered opioids show decreased potency and efficacy in the treatment of neuropathic pain. As reported previously, morphine stimulates spinal opioid receptors to effect adenosine release, which acts at adenosine receptors to produce analgesia. The authors hypothesized that morphine induces less adenosine release in neuropathic compared with normal rats, explaining its reduced potency and efficacy. Methods Sprague-Dawley rats (200-250 g) were divided into three groups: no surgery (n = 52), sham surgery (n = 20), or left L5 and L6 spinal nerve ligation (n = 64). Two weeks after surgery, mechanical hypersensitivity of the left hind paw was verified. For each experiment, a crude synaptosomal P2 suspension was prepared by homogenizing cervical and lumbar dorsal spinal cord halves from four rats, followed by differential centrifugation, and aliquots incubated with morphine sulfate from 10(-8) to 10(-4) m alone or in presence of 10(-5) m dipyridamole. Extrasynaptosomal concentrations of adenosine were analyzed by high-pressure liquid chromatography. Results Synaptosomal release of adenosine in the absence of morphine was similar between groups. Morphine produced a concentration-dependent adenosine release, which was less in synaptosomes from dorsal lumbar spinal cord in spinal nerve ligation compared with normal or sham animals. This reduction was removed by adding dipyridamole. Conclusion Morphine normally stimulates spinal release of adenosine, a potent antihypersensitivity compound. Because this effect of morphine is diminished in spinal nerve ligation animals, one explanation for decreased efficacy and potency of opioids in the treatment of neuropathic pain may be a dipyridamole-sensitive disruption in the opioid-adenosine link in the spinal cord.

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.

Antiallodynic Effects of Intrathecal Areca Nut for Spinal Nerve-Ligated and Chemotherapy-Induced Neuropathic Pain in Rats

Pharmacology ◽  
2018 ◽  
Vol 102 (5-6) ◽  
pp. 332-338 ◽  
Author(s):  
Hyung Gon Lee ◽  
Ji A Song ◽  
Dong Soo Han ◽  
Kyeong Wan Woo ◽  
Myung Ha Yoon
Keyword(s):  
Neuropathic Pain ◽  
Adrenergic Receptors ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Areca Nut ◽  
Sprague Dawley ◽  
Once Daily ◽  
Spinal Nerves ◽  
Sprague Dawley Rats ◽  
Von Frey Filaments

This study examined the effects of intrathecal areca nut on spinal nerve-ligated and chemotherapy-induced neuropathic pain (NP), and investigated the relevance of spinal 5-hydroxytryptamine (5-HT) and α2-adrenergic receptors to those effects. For drug administration, intrathecal catheters were inserted into the subarachnoid space of male Sprague-Dawley rats. NP was induced either by spinal nerve ligation (left spinal nerves L5 and L6) or by chemotherapeutic injection (intraperitoneal cisplatin, 2 mg/kg/day, once daily for 4 days). Paw withdrawal thresholds (PWT) were mechanically assessed using von Frey filaments. The involvement of 5-HT and α2-adrenergic receptors in antiallodynia was determined using antagonists with the following receptor specificities: nonselective 5-HT (dihydroergocristine), 5-HT7 (SB269970), nonselective α2-adrenoceptor (yohimbine), α-2A (BRL 44408), α-2B (ARC 239), and α-2C (JP 1302). Intrathecal areca nut significantly increased the PWT in both spinal nerve-ligated and chemotherapy-induced NP (‡ p < 0.001). Intrathecal dihydroergocristine, SB269970, yohimbine, BRL 44408, ARC 239, and JP 1302 significantly reversed the antiallodynic effects of areca nut in both NP states (‡ p < 0.001). Collectively, intrathecal areca nut suppressed mechanical allodynia induced by spinal nerve ligation and cisplatin injection. Furthermore, spinal 5-HT7 receptor and α2A, α2B, and α2C-adrenoceptors contributed to the antiallodynic effects of areca nut.

scholarly journals A 3D map of the hindlimb motor representation in the lumbar spinal cord in Sprague Dawley rats

2016 ◽  
Vol 14 (1) ◽  
pp. 016007 ◽  
Author(s):  
Jordan A Borrell ◽  
Shawn B Frost ◽  
Jeremy Peterson ◽  
Randolph J Nudo
Keyword(s):  
Spinal Cord ◽  
Lumbar Spinal Cord ◽  
Sprague Dawley ◽  
Motor Representation ◽  
Sprague Dawley Rats ◽  
Lumbar Spinal

Increased Expression of Cyclooxygenase and Nitric Oxide Isoforms, and Exaggerated Sensitivity to Prostaglandin E2, in the Rat Lumbar Spinal Cord 3 Days after L5–L6 Spinal Nerve Ligation

2006 ◽  
Vol 104 (2) ◽  
pp. 328-337 ◽  
Author(s):  
Darren D. O’Rielly ◽  
Christopher W. Loomis
Keyword(s):  
Nitric Oxide ◽  
Spinal Cord ◽  
Neuropathic Pain ◽  
Glutamate Release ◽  
Spinal Nerve ◽  
Spinal Nerve Ligation ◽  
Withdrawal Threshold ◽  
Enhanced Sensitivity ◽  
Sham Surgery ◽  
Inducible Nos

Background Spinal prostaglandins seem to be important in the early pathogenesis of experimental neuropathic pain. Here, the authors investigated changes in the expression of cyclooxygenase and nitric oxide synthase (NOS) isoforms in the lumbar, thoracic, and cervical spinal cord and the pharmacologic sensitivity to spinal prostaglandin E2 (PGE2) after L5-L6 spinal nerve ligation (SNL). Methods Male Sprague-Dawley rats, fitted with intrathecal catheters, underwent SNL or sham surgery 3 days before experimentation. Paw withdrawal threshold was monitored for up to 20 days. Immunoblotting, spinal glutamate release, and behavioral testing were examined 3 days after SNL. Results Allodynia (paw withdrawal threshold &lt; or = 4 g) was evident 1 day after SNL and remained stable for 20 days. Paw withdrawal threshold was unchanged (P &gt; 0.05) from baseline (&gt; 15 g) after sham surgery except for a small but significant decrease on day 20. Cyclooxygenase 2, neuronal NOS, and inducible NOS were significantly increased in the ipsilateral lumbar dorsal horn after SNL. Expression in the contralateral dorsal horn and ventral horns (lumbar segments) or bilaterally (thoracic and cervical segments) was unchanged from sham controls. This was accompanied by a significant decrease in both the EC50 of PGE2-evoked glutamate release and the ED50 of PGE2 on brush-evoked allodynia. Enhanced sensitivity to PGE2 was localized to lumbar segments of SNL animals and attenuated by SC-51322 or S(+)-ibuprofen, but not R(-)-ibuprofen (100 mum). Conclusion The increased expression of cyclooxygense-2, neuronal NOS, and inducible NOS and the enhanced sensitivity to PGE2 in spinal segments affected by SNL support the hypothesis that spinal prostanoids play an early pathogenic role in experimental neuropathic pain.

scholarly journals Melanocortin 4 Receptor Mediates Neuropathic Pain Through p38MAPK in Spinal Cord

2012 ◽  
Vol 39 (4) ◽  
pp. 458-464 ◽  
Author(s):  
Haichen Chu ◽  
Jiangling Xia ◽  
Hongmei Xu ◽  
Zhao Yang ◽  
Jie Gao ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Time Course ◽  
Lumbar Spinal Cord ◽  
Enzyme Linked Immunosorbent Assay ◽  
Melanocortin 4 Receptor ◽  
Male Wistar Rats ◽  
Underlying Mechanisms ◽  
Lumbar Spinal ◽  
Somatosensory Nervous System

Background:Neuropathic pain is characterised by spontaneous ongoing or shooting pain and evoked amplified pain responses after noxious or non-noxious stimuli. Neuropathic pain develops as a result of lesions or disease affecting the somatosensory nervous system either in the periphery or centrally. Melanocortin 4 receptor (MC4R) plays an important role in the initiation of neuropathic pain but the underlying mechanisms are still unclear.Methods:Adult male Wistar rats were given chronic constriction injury (CCI) or sham operations. Part of CCI rats were intrathecally treated with HS014 (MC4R antagonist) or SB203580 (p38MAPK inhibitor). On the third, seventh and fourteenth day, the thermal threshold of operated paws was tested. In addition, the MC4R or phosphorylated p38MAPK (p-p38MAPK) levels of lumbar spinal cord were tested with ELISA (enzyme-linked immunosorbent assay), western blot and immunohistochemistry.Results:Here we demonstrate that (1) both HS014 and SB203580 reduced CCI reduced hyperalgesia (2) p-p38MAPK was increased after CCI with a time course parallel to that of the MC4R change, (3) The p38 activation was prevented by blocking MC4R with an antagonist HS014, but MC4R-IR was not prevented by SB203580. (4) MC4R and p-p38MAPK were located in the same cells.Conclusion:The mechanisms of neuropathic pain mediated by MC4R is related to the inhibition of p38MAPK activation. P38MAPK may be a downstream of MC4R.

scholarly journals Alterations in the Anandamide Metabolism in the Development of Neuropathic Pain

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Natalia Malek ◽  
Mateusz Kucharczyk ◽  
Katarzyna Starowicz
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Mrna Level ◽  
Inhibitory Effect ◽  
Lumbar Spinal Cord ◽  
Local Synthesis ◽  
Time Points ◽  
Pain Pathways ◽  
Lumbar Spinal ◽  
Synthesis And Degradation

Endocannabinoids (EC), particularly anandamide (AEA), released constitutively in pain pathways might be accountable for the inhibitory effect on nociceptors. Pathogenesis of neuropathic pain may reflect complex remodeling of the dorsal root ganglia (DRGs) and spinal cord EC system. Multiple pathways involved both in the biosynthesis and degradation of AEA have been suggested. We investigated the local synthesis and degradation features of AEA in DRGs and spinal cord during the development and maintenance of pain in a model of chronic constriction injury (CCI). All AEA synthesis and degradation enzymes are present on the mRNA level in DRGs and lumbar spinal cord of intact as well as CCI-treated animals. Deregulation of EC system components was consistent with development of pain phenotype at days 3, 7, and 14 after CCI. The expression levels of enzymes involved in AEA degradation was significantly upregulated ipsilateral in DRGs and spinal cord at different time points. Expression of enzymes of the alternative, sPLA2-dependent and PLC-dependent, AEA synthesis pathways was elevated in both of the analyzed structures at all time points. Our data have shown an alteration of alternative AEA synthesis and degradation pathways, which might contribute to the variation of AEA levels and neuropathic pain development.

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