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Protraction of neuropathic pain by morphine is mediated by spinal damage associated molecular patterns (DAMPs) in male rats.

ABSTRACT: We have recently reported that a short course of morphine, starting 10days after sciatic chronic constriction injury (CCI), prolonged the duration of mechanical allodynia for months after morphine ceased. Maintenance of this morphine-induced persistent sensitization was dependent on spinal NOD-like receptor protein 3 (NLRP3) inflammasomes-protein complexes that proteolytically activate interleukin-1β (IL-1β) via caspase-1. However, it is still unclear how NLRP3 inflammasome signaling is maintained long after morphine is cleared. Here, we demonstrate that spinal levels of the damage associated molecular patterns (DAMPs) high mobility group box 1 (HMGB1) and biglycan are elevated during morphine-induced persistent sensitization in male rats; that is, 5weeks after cessation of morphine dosing. We also show that HMGB1 and biglycan levels are at least partly dependent on the initial activation of caspase-1, as well as Toll like receptor 4 (TLR4) and the purinergic receptor P2X7R-receptors responsible for priming and activation of NLRP3 inflammasomes. Finally, pharmacological attenuation of the DAMPs HMGB1, biglycan, heat shock protein 90 and fibronectin persistently reversed morphine-prolonged allodynia. We conclude that after peripheral nerve injury, morphine treatment results in persistent DAMP release via TLR4, P2X7R and caspase-1, which are involved in formation/activation of NLRP3 inflammasomes. These DAMPs are responsible for maintaining persistent allodynia, which may be due to engagement of a positive feedback loop, in which NLRP3 inflammasomes are persistently activated by DAMPs signaling at TLR4 and P2X7R.

SUBMITTER: Grace PM

PROVIDER: S-EPMC5832500 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Protraction of neuropathic pain by morphine is mediated by spinal damage associated molecular patterns (DAMPs) in male rats.

Grace Peter M PM Strand Keith A KA Galer Erika L EL Rice Kenner C KC Maier Steven F SF Watkins Linda R LR

Brain, behavior, and immunity 20170830

We have recently reported that a short course of morphine, starting 10days after sciatic chronic constriction injury (CCI), prolonged the duration of mechanical allodynia for months after morphine ceased. Maintenance of this morphine-induced persistent sensitization was dependent on spinal NOD-like receptor protein 3 (NLRP3) inflammasomes-protein complexes that proteolytically activate interleukin-1β (IL-1β) via caspase-1. However, it is still unclear how NLRP3 inflammasome signaling is maintain ...[more]

PMID: 28860068

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Project description:Neuropathic pain, a debilitating pain condition, is a common consequence of damage to the nervous system. Optimal treatment of neuropathic pain is a major clinical challenge because the underlying mechanisms remain unclear and currently available treatments are frequently ineffective. Emerging lines of evidence indicate that peripheral nerve injury converts resting spinal cord glia into reactive cells that are required for the development and maintenance of neuropathic pain. However, the mechanisms underlying reactive astrogliosis after nerve injury are largely unknown. In the present study, we investigated cell proliferation, a critical process in reactive astrogliosis, and determined the temporally restricted proliferation of dorsal horn astrocytes in rats with spinal nerve injury, a well-known model of neuropathic pain. We found that nerve injury-induced astrocyte proliferation requires the Janus kinase-signal transducers and activators of transcription 3 signalling pathway. Nerve injury induced a marked signal transducers and activators of transcription 3 nuclear translocation, a primary index of signal transducers and activators of transcription 3 activation, in dorsal horn astrocytes. Intrathecally administering inhibitors of Janus kinase-signal transducers and activators of transcription 3 signalling to rats with nerve injury reduced the number of proliferating dorsal horn astrocytes and produced a recovery from established tactile allodynia, a cardinal symptom of neuropathic pain that is characterized by pain hypersensitivity evoked by innocuous stimuli. Moreover, recovery from tactile allodynia was also produced by direct suppression of dividing astrocytes by intrathecal administration of the cell cycle inhibitor flavopiridol to nerve-injured rats. Together, these results imply that the Janus kinase-signal transducers and activators of transcription 3 signalling pathway are critical transducers of astrocyte proliferation and maintenance of tactile allodynia and may be a therapeutic target for neuropathic pain.

Project description:BackgroundNeuropathic pain is a complex condition resulting from damage or disease in the somatosensory nervous system, causing significant physical and emotional distress. Despite its profound impact, the underlying causes and treatment methods of neuropathic pain remain poorly understood.MethodsTo better understand this condition, we conducted the first study examining the spatial distribution and dynamic expression changes of N-glycan molecules that play a crucial role in nervous system function and sustainable pain signal transmission across multiple regions of the spinal cord and brain in an experimentally induced neuropathic pain model, using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI).ResultsOur findings revealed that neuropathic pain induces dynamic changes in N-glycan expression across various regions of the spinal cord and brain. Notably, we discovered distinct glycan profiles between the spinal cord and brain, with N-glycans downregulated in the spinal cord and upregulated in the brain at a time when mechanical allodynia is sustained following spinal nerve ligation (SNL). Significant changes in N-glycan expression were observed in the dorsal laminae IV/V/VI and the ventral horn of the spinal cord. Additionally, marked changes were detected in the contralateral regions of the primary sensory cortex (S1) and the primary sensory cortex hindlimb area (S1HL). Furthermore, we observed significant upregulation of N-glycan expression in the thalamus, anterior cingulate cortex (ACC), and medial prefrontal cortex (mPFC) in both ipsilateral and contralateral regions of the brain.ConclusionsGiven that N-glycans are implicated in pain processing yet their precise role remains unclear, our study highlights the need to explore N-glycosylation with a more nuanced focus on both the spinal cord and brain. This research provides new insights into the mechanisms of persistent neuropathic pain and lays the groundwork for future studies and the development of targeted therapeutic strategies.

Project description:In the present study, the ability of baicalin to relieve neuropathic pain due to spinal nerve ligation in rats was explored, and the relationship between baicalin and ?2-adrenoceptors (?2-AR) was determined. The neuropathic pain model was established by ligating the L5-L6 spinal nerves in Sprague-Dawley rats. Several ?2-AR antagonists were injected into the intramedullary sheath to evaluate the role of baicalin in neuropathic pain. The antagonists included nonselective ?2-AR antagonist idazoxan, ?2a-AR antagonist BRL 44408, ?2b-AR antagonist ARC 239 and ?2c-AR antagonist JP 1302. The rats were divided into an untreated control group, saline group, baicalin group and baicalin + ?2-AR antagonist groups. Paw withdrawal threshold (PWT) was tested to assess the level of pain felt by the rats. The levels of ?2-AR mRNA were tested by reverse transcription-quantitative PCR. Inflammatory factors, including tumor necrosis factor (TNF)-?, interleukin (IL)-6, IL-17 and IL-1?, were analyzed by ELISA. The histopathological changes were assessed by hematoxylin and eosin staining. Flow cytometry was used to examine the percentage of CD4+ peripheral blood mononuclear cells (PBMCs). Compared with the saline group, the PWT value increased after treating with baicalin. However, intrathecal injection of ?2-AR antagonist reversed the antinociceptive effects of baicalin. Compared with the saline group, the expression of ?2a-AR and ?2c-AR mRNA was upregulated significantly in the baicalin group (P<0.05). Levels of ?2-AR mRNA were also decreased in the baicalin + idazoxan group compared with the baicalin group (P<0.05). The levels of TNF-?, IL-6, IL-17 and IL-1? were raised after treatment with baicalin. In addition, baicalin treatment ameliorated the histological damage in the spinal cord. The percentage of CD4+ PBMCs was increased in the saline group compared with the control group (P<0.05). Compared with the baicalin group, the percentage of CD4+ PBMCs was raised after treatment with the ?2-AR antagonists. In conclusion, intrathecal injection of baicalin produced an antiallodynic effect in a spinal nerve ligation-induced neuropathic pain model. The mechanism may be related to the regulation of a2-AR expression.

Dataset Information

Protraction of neuropathic pain by morphine is mediated by spinal damage associated molecular patterns (DAMPs) in male rats.

Publications

Protraction of neuropathic pain by morphine is mediated by spinal damage associated molecular patterns (DAMPs) in male rats.

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