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The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice
Published on: July 16, 2014
Protraction of neuropathic pain by morphine is mediated by spinal damage associated molecular patterns (DAMPs) in
Peter M Grace1, Keith A Strand2, Erika L Galer2
1Department of Psychology and Neuroscience, and The Center for Neuroscience, University of Colorado, Boulder, CO, USA; Discipline of Pharmacology, School of Medicine, University of Adelaide, Adelaide, SA, Australia.
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.
Insights
Morphine treatment after nerve injury causes persistent pain sensitization by activating spinal NLRP3 inflammasomes. This involves damage-associated molecular patterns (DAMPs) like HMGB1 and biglycan, which maintain the pain state.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Peripheral nerve injury can lead to chronic pain conditions like mechanical allodynia.
- Morphine treatment, even short-term, can paradoxically prolong this allodynia via spinal mechanisms.
- The role of the NLRP3 inflammasome in maintaining this morphine-induced sensitization is known, but the long-term signaling triggers are unclear.
Purpose of the Study:
- To investigate the mechanisms maintaining spinal NLRP3 inflammasome activation and persistent allodynia after morphine cessation in a rat model.
- To identify specific damage-associated molecular patterns (DAMPs) involved in this sustained sensitization.
- To evaluate the therapeutic potential of targeting these DAMPs.
Main Methods:
- Sciatic chronic constriction injury (CCI) in male rats followed by a short course of morphine.
- Measurement of spinal DAMPs (HMGB1, biglycan, HSP90, fibronectin) and inflammasome components (caspase-1, IL-1β) at various time points.
- Pharmacological inhibition of DAMPs, TLR4, P2X7R, and caspase-1.
- Assessment of mechanical allodynia using behavioral tests.
Main Results:
- Spinal HMGB1 and biglycan levels were elevated 5 weeks after morphine cessation in CCI rats.
- These DAMP elevations were dependent on caspase-1, TLR4, and P2X7R activation.
- Pharmacological blockade of HMGB1, biglycan, HSP90, and fibronectin reversed the morphine-prolonged allodynia.
- Evidence suggests a positive feedback loop involving DAMPs, TLR4, P2X7R, and NLRP3 inflammasomes.
Conclusions:
- Morphine treatment following peripheral nerve injury induces long-lasting pain sensitization through sustained activation of spinal NLRP3 inflammasomes.
- Elevated DAMPs (HMGB1, biglycan) are critical mediators in this process, signaling through TLR4 and P2X7R.
- Targeting these DAMPs offers a promising therapeutic strategy for persistent post-injury pain.
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