Inhibition of microglial activity alters spinal wide dynamic range neuron discharge and reduces microglial Toll‐like receptor 4 expression in neuropathic rats

Abstract

SUMMARYIt is believed that neuropathic pain results from aberrant neuronal discharges although some evidence suggests that the activation of glia cells contributes to pain after an injury to the nervous system. This study aimed to evaluate the role of microglial activation on the hyper-responsiveness of wide dynamic range neurons (WDR) and Toll-like receptor 4 (TLR4) expressions in a chronic constriction injury (CCI) model of neuropathic pain in rats. Adult male Wistar rats (230 AE 30 g) underwent surgery for induction of CCI neuropathy. Six days after surgery, administration of minocycline (10, 20, and 40 mg/kg, i.p.) was initiated and continued until day 14. After administration of the last dose of minocycline or saline, a behavioral test was conducted, then animals were sacrificed and lumbar segments of the spinal cord were collected for Western blot analysis of TLR4 expression. The electrophysiological properties of WDR neurons were investigated by single unit recordings in separate groups. The findings showed that after CCI, in parallel with thermal hyperalgesia, the expression of TLR4 in the spinal cord and the evoked response of the WDR neurons to electrical, mechanical, and thermal stimulation significantly increased. Post-injury administration of minocycline effectively decreased thermal hyperalgesia, TLR4 expression, and hyperresponsiveness of WDR neurons in CCI rats. The results of this study indicate that post-injury, repeated administration of minocycline attenuated neuropathic pain by suppressing microglia activation and reducing WDR neuron hyperresponsiveness. This study confirms that post-injury modulation of microglial activity is a new strategy for treating neuropathic pain.

Glial activation in the periaqueductal gray promotes descending facilitation of neuropathic pain through the p38 MAPK signaling pathway

“…C,E,G,I, B,D,F,H). Immunohistochemistry and Western blot studies showed that glial cells displayed the same level of activation in sham and in naive rats (data not shown), which is in agreement with previous reports (Wenzhan et al, ; Nazemi et al, ). In comparison with naive and sham groups, PAG sections exhibited increased Iba1 immunostaining along with morphological changes that showed fewer ramified and thickened processes following CCI surgery (Fig.…”

Minocycline Prevents the Development of Mechanical Allodynia in Mouse Models of Vincristine-Induced Peripheral Neuropathy

“…Minocycline has previously been suggested to exert its anti-inflammatory actions via modulation of TLR4 expression (Nazemi et al, 2015). Thus, to further confirm whether TLR4 signaling contributes to the development of mechanical hypersensitivity and paw swelling following local vincristine administration, we also assessed the development of VIPN in Tlr4 −/− mice.…”

Targeting macrophage and microglia activation with colony stimulating factor 1 receptor inhibitor is an effective strategy to treat injury-triggered neuropathic pain

“… 42 Administration of minocycline in nerve-injured animals also effectively reduces TLR4 expression, which suppresses microglia activation in spinal cord and hyper-responsive wide dynamic range neurons. 43 Minocycline treatment also inhibits the expression of MMP-9 and pro-nociceptive molecules such as IL-6 and IL-18 in the spinal cord while anti-nociceptive molecules (IL-4, IL-10) are unaffected. 44 Depletion of spinal microglia with selectively immunotoxin, Mac-1 saporin was able to prevent and reverse neuropathic pain behavior.…”