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

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 Aδ-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.

Microglia in the spinal cord and neuropathic pain

“…Mechanisms underlying the spatial‐specific activation of microglia in the dorsal horn remain to be determined. However, the area in the spinal dorsal horn receiving damaged primary afferent sensory neurons matches that having markedly activated microglia, therefore, microglial activation requires a signal(s) related to ‘nerve injury.’ Indeed, blocking peripheral input from primary afferent fibers by bupivacaine inhibits microglial activation in the dorsal horn after PNI33. In STZ‐treated diabetic mice, Suzuki et al 23.…”

P2X4R+ microglia drive neuropathic pain

“…Release of ATP from the central terminals of largediameter, myelinated primary sensory neurons 39 could account for P2X4R-dependent p38 MAP kinase (mitogen-activated protein kinase) activation in microglia. Certainly activity in large myelinated fibers is important for these changes, as only a full local anesthetic blockade of the peripheral nerve before injury is sufficient to prevent subsequent spinal microglial proliferation and p38 MAP kinase activation, whereas selectively blocking smalldiameter, unmyelinated nociceptive fibers is ineffectual 40 . Although still unproven, involvement of large-diameter sensory afferents would also account for the nerve injuryevoked responses of microglia in the gracile nucleus, as well as in the dorsal horn, both sites of termination of large-diameter fibers.…”

Microglia–neuronal signalling in neuropathic pain hypersensitivity 2.0

“…Propagation of action potentials in primary sensory neurons into the spinal cord is likely a critical step as the microglia response per se requires action potentials in primary afferents 17 . The subsequent signalling to spinal microglia has been suggested to involve a number of ligand/receptor systems, including fibronectin/integrin 18,19 , MCP1/ CCR2 20 , interferon/IFG receptor signalling 21 .…”