Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury - PubMed (original) (raw)

Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury

Marc R Suter et al. Mol Pain. 2009.

Abstract

Background: After peripheral nerve injury, spontaneous ectopic activity arising from the peripheral axons plays an important role in inducing central sensitization and neuropathic pain. Recent evidence indicates that activation of spinal cord microglia also contributes to the development of neuropathic pain. In particular, activation of p38 mitogen-activated protein kinase (MAPK) in spinal microglia is required for the development of mechanical allodynia. However, activity-dependent activation of microglia after nerve injury has not been fully addressed. To determine whether spontaneous activity from C- or A-fibers is required for microglial activation, we used resiniferatoxin (RTX) to block the conduction of transient receptor potential vanilloid subtype 1 (TRPV1) positive fibers (mostly C- and Adelta-fibers) and bupivacaine microspheres to block all fibers of the sciatic nerve in rats before spared nerve injury (SNI), and observed spinal microglial changes 2 days later.

Results: SNI induced robust mechanical allodynia and p38 activation in spinal microglia. SNI also induced marked cell proliferation in the spinal cord, and all the proliferating cells (BrdU+) were microglia (Iba1+). Bupivacaine induced a complete sensory and motor blockade and also significantly inhibited p38 activation and microglial proliferation in the spinal cord. In contrast, and although it produced an efficient nociceptive block, RTX failed to inhibit p38 activation and microglial proliferation in the spinal cord.

Conclusion: (1) Blocking peripheral input in TRPV1-positive fibers (presumably C-fibers) is not enough to prevent nerve injury-induced spinal microglial activation. (2) Peripheral input from large myelinated fibers is important for microglial activation. (3) Microglial activation is associated with mechanical allodynia.

PubMed Disclaimer

Figures

Figure 1

Effects of nerve block with bupivacaine microspheres (Bup, A) and resiniferatoxin (RTX, B) on heat sensitivity before and two days after spared nerve injury (SNI). Both bupivacaine and RTX increase the paw withdrawal latencies in injured and non injured rats. Note a decrease in latency after SNI. Baseline pain sensitivity was tested before drug treatment and nerve injury *p < 0.05, **p < 0.01.

Figure 2

Effects of nerve block with bupivacaine microspheres (Bup, A) and resiniferatoxin (RTX, B) on mechanical sensitivity before and two days after spared nerve injury (SNI). SNI-induced mechanical allodynia, i.e. decrease in paw withdrawal threshold, is not prevented by RTX treatment. Baseline pain sensitivity was tested before drug treatment and nerve injury *p < 0.05, **p < 0.01.

Figure 3

SNI induces microglial proliferation in the spinal cord. (A) Bromodeoxyuridine (BrdU) staining in the dorsal horn of the spinal cord two days after SNI. There is a dramatic increase in number of BrdU-positive profiles in the dorsal horn ipsilateral to nerve injury. Scale bar, 200 μm. (B-D) Enlargement of the ipsilateral medial dorsal horn (square indicated in A) showing co-localization of BrdU with the microglial marker Iba1. Scale bars, 50 μm.

Figure 4

Confocal microscopy images show BrdU expression in spinal microglia two days after SNI. (A-C) Colocalization of BrdU and Iba1 in the medial superficial spinal cord. Scale bars, 50 μm. (D) Stack of confocal images (2 μm apart) from a double-labeled cell enlarged from a square in C. (E) Merge of all images in D. Scale bars, 20 μm.

Figure 5

Bupivacaine but not resiniferatoxin reduces cell proliferation in the spinal cord dorsal horn after SNI. (A-D) BrdU immunostaining in the dorsal horn of control rats (A) and SNI rats receiving vehicle (B), RTX (C), and bupivacaine (Bup, D). (E) Number of BrdU-positive cell profiles in the dorsal horn: Left, effects of RTX on SNI-induced cell proliferation. Right: effects of bupivacaine on SNI-induced cell proliferation *p < 0.05, **p < 0.01, ns = no significance. Scale bar 200 μm. n = 3-5.

Figure 6

Bupivacaine but not resiniferatoxin reduces the phosphorylation of p38 MAPK in the spinal cord dorsal horn after SNI. (A-D) p-p38 immunostaining in the dorsal horn of control rats (A) and SNI rats receiving vehicle (B), RTX (C), and bupivacaine (Bup, D). (E) Number of p-p38-positive cell profiles in the dorsal horn: Left, effects of RTX on SNI-induced cell proliferation. Right: effects of bupivacaine on SNI-induced cell proliferation *p < 0.05, **p < 0.01, ns = no significance. Scale bar 100 μm. n = 3-5.

Cited by

Rapamycin reduces orofacial nociceptive responses and microglial p38 mitogen-activated protein kinase phosphorylation in trigeminal nucleus caudalis in mouse orofacial formalin model.
Yeo JH, Kim SJ, Roh DH. Yeo JH, et al. Korean J Physiol Pharmacol. 2021 Jul 1;25(4):365-374. doi: 10.4196/kjpp.2021.25.4.365. Korean J Physiol Pharmacol. 2021. PMID: 34187953 Free PMC article.
Exogenous nerve growth factor protects the hypoglossal nerve against crush injury.
Fan LY, Wang ZC, Wang P, Lan YY, Tu L. Fan LY, et al. Neural Regen Res. 2015 Dec;10(12):1982-8. doi: 10.4103/1673-5374.172316. Neural Regen Res. 2015. PMID: 26889186 Free PMC article.
Deconstructing the neuropathic pain phenotype to reveal neural mechanisms.
von Hehn CA, Baron R, Woolf CJ. von Hehn CA, et al. Neuron. 2012 Feb 23;73(4):638-52. doi: 10.1016/j.neuron.2012.02.008. Neuron. 2012. PMID: 22365541 Free PMC article. Review.
Targeting p38 Mitogen-activated Protein Kinase to Reduce the Impact of Neonatal Microglial Priming on Incision-induced Hyperalgesia in the Adult Rat.
Schwaller F, Beggs S, Walker SM. Schwaller F, et al. Anesthesiology. 2015 Jun;122(6):1377-90. doi: 10.1097/ALN.0000000000000659. Anesthesiology. 2015. PMID: 25859904 Free PMC article.
Isolated nociceptors reveal multiple specializations for generating irregular ongoing activity associated with ongoing pain.
Odem MA, Bavencoffe AG, Cassidy RM, Lopez ER, Tian J, Dessauer CW, Walters ET. Odem MA, et al. Pain. 2018 Nov;159(11):2347-2362. doi: 10.1097/j.pain.0000000000001341. Pain. 2018. PMID: 30015712 Free PMC article.

References

1. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006;367:1618–1625. doi: 10.1016/S0140-6736(06)68700-X. - DOI - PubMed
1. Kelly DJ, Ahmad M, Brull SJ. Preemptive analgesia I: physiological pathways and pharmacological modalities. Can J Anaesth. 2001;48:1000–1010. doi: 10.1007/BF03016591. - DOI - PubMed
1. Devor M, Seltzer Z. Pathophysiology of damaged nerves in relation to chronic pain. In: Wall PD, Melzack R, editor. Textbook of Pain. Edinburgh: Churchill Livingstone; 1999. pp. 129–164.
1. Ma C, Shu Y, Zheng Z, Chen Y, Yao H, Greenquist KW, White FA, LaMotte RH. Similar electrophysiological changes in axotomized and neighboring intact dorsal root ganglion neurons. J Neurophysiol. 2003;89:1588–1602. doi: 10.1152/jn.00855.2002. - DOI - PubMed
1. Wu G, Ringkamp M, Hartke TV, Murinson BB, Campbell JN, Griffin JW, Meyer RA. Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers. J Neurosci. 2001;21:RC140. - PMC - PubMed

Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury - PubMed (original) (raw)