Mirror-image pain is mediated by nerve growth factor produced from tumor necrosis factor alpha-activated satellite glia after peripheral nerve injury

Abstract

Mirror-image pain is characterized by mechanical hypersensitivity on the uninjured mirror-image side. Recent reports favor central mechanisms, but whether peripheral mechanisms are involved remains unclear. We used unilateral spinal nerve ligation (SNL) to induce mirror-image pain in rats. On the mirror-image (contralateral) side, we found that satellite glia in the dorsal root ganglion (DRG) were activated, whereas macrophages/Schwann cells in the DRG and astrocytes/oligodendrocytes/microglia in the dorsal spinal cord were not. Subsequently, an increase in nerve growth factor (NGF) was detected in the contralateral DRG, and NGF immunoreactivity was concentrated in activated satellite glia. These phenomena were abolished if fluorocitrate (a glial inhibitor) was intrathecally injected before SNL. Electrophysiological recordings in cultured small DRG neurons showed that exogenous NGF enhanced nociceptor excitability. Intrathecal injection of NGF into naive rats induced long-lasting mechanical hypersensitivity, similar to SNL-evoked mirror-image pain. Anti-NGF effectively relieved SNL-evoked mirror-image pain. In the contralateral DRG, the SNL-evoked tumor necrosis factor alpha (TNF-α) increase, which started later than in the ipsilateral DRG and cerebrospinal fluid, occurred earlier than satellite glial activation and the NGF increase. Intrathecal injection of TNF-α into naive rats not only activated satellite glia to produce extra NGF in the DRG but also evoked mechanical hypersensitivity, which could be attenuated by anti-NGF injection. These results suggest that after SNL, satellite glia in the contralateral DRG are activated by TNF-α that diffuses from the injured side via cerebrospinal fluid, which then activates satellite glia to produce extra NGF to enhance nociceptor excitability, which induces mirror-image pain.

Improvement of spinal non-viral IL-10gene delivery by D-mannose as a transgene adjuvant to control chronic neuropathic pain

“…The observed bilateral behavioral changes that correspond to bilateral cytokine alterations following peripheral neuropathy supports observations from prior reports [29,54-56,90], with other reports demonstrating corresponding changes in glial activation [55,56,91-93]. While neuropathic pain resulting from inflammation and/or trauma to peripheral nerves is most widely characterized as arising from the body region in which the trauma/inflammation occurred, pain may also be perceived as arising from the healthy contralateral (‘mirror-image’) body region [91].…”

Calpain-2 contributes to neuropathic pain following motor nerve injury via up-regulating interleukin-6 in DRG neurons

“…In fact, unilateral nerve injury or inflammation also activates satellite glia and macrophages in contralateral DRG of animals with mirror pain (Hatashita et al, 2008;Xie et al, 2006;Zhou et al, 1996). TNF-a that diffuses from the injured side via cerebrospinal fluid (CSF) activates satellite glia in contralateral DRG, which then produces extra nerve growth factor to enhance nociceptor excitability after spinal nerve ligation (Cheng et al, 2014). In this report, the contralateral increases of calpain-2 (Fig.…”

“…3B) and IL-6 ( Fig. 4B) soon after L5-VRT might result from the ipsilateral diffusion by CSF (Cheng et al, 2014) or blood way (Zanjani et al, 2006).…”

Bilateral distribution of anterior cutaneous nerve entrapment syndrome (ACNES): are clinical features and outcomes comparable to unilateral ACNES?

“…A contralateral response might be induced by a glial cell inflammatory response with subsequent release of cytokines leading to activation of central neural nociceptive pathways 24. However, one study showed a peripheral pathway where unilateral nerve injury led to production of tumor necrosis factor alpha (TNF-α) in the dorsal root ganglion (DRG) on the affected side 25. It was hypothesized that TNF-α may diffuse via cerebrospinal fluid toward the contralateral DRG.…”

“…It was hypothesized that TNF-α may diffuse via cerebrospinal fluid toward the contralateral DRG. TNF-α subsequently activates satellite glia to produce nerve growth factor leading to long-lasting mechanical hypersensitivity leading to mirroring of pain 25. While there is thus evidence supporting both mechanisms, further studying of this rare phenomenon is warranted to uncover transmedian signaling mechanisms as well to improve our understanding of how brain activity “connects” both sides of the body.…”