Inhibition of glial activation in rostral ventromedial medulla attenuates mechanical allodynia in a rat model of cancer-induced bone pain

Abstract

Descending nociceptive modulation from the supraspinal structures plays an important role in cancer-induced bone pain (CIBP). Rostral ventromedial medulla (RVM) is a critical component of descending nociceptive facilitation circuitry, but so far the mechanisms are poorly known. In this study, we investigated the role of RVM glial activation in the descending nociceptive facilitation circuitry in a CIBP rat model. CIBP rats showed significant activation of microglia and astrocytes, and also up-regulation of phosphorylated p38 mitogen-activated protein kinase (p38 MAPK) and pro-inflammatory mediators released by glial cells (IL-1β, IL-6, TNF-α and brain-derived neurotrophic factor) in the RVM. Stereotaxic microinjection of the glial inhibitors (minocycline and fluorocitrate) into CIBP rats' RVM could reverse the glial activation and significantly attenuate mechanical allodynia in a time-dependent manner. RVM microinjection of p38 MAPK inhibitor (SB203580) abolished the activation of microglia, reversed the associated up-regulation of pro-inflammatory mediators and significantly attenuated mechanical allodynia. Taken together, these results suggest that RVM glial activation is involved in the pathogenesis of CIBP. RVM microglial p38 MAPK signaling pathway is activated and leads to the release of downstream pro-inflammatory mediators, which contribute to the descending facilitation of CIBP.

Minocycline attenuates bone cancer pain in rats by inhibiting NF-κB in spinal astrocytes

“…Rat BCP models were established using previously described methods [7,[23][24][25] . In brief, under anesthesia with pentobarbital sodium (40 mg/kg, ip), rats were placed in a supine position, and the right leg was shaved and disinfected with 7% iodine.…”

Cancer-induced bone pain: Mechanisms and models

“…This provides evidence that NGF/TrkA signaling over other neurotrophin subtypes may be more important in cancer pain [46, 65] Recent studies on BDNF have demonstrated a role in the induction and maintenance of behavioral hypersensitivity in a rat model of CIBP by BDNF modulating the NMDA subunit 1 (NR1) at the level of the spinal cord and DRG [99]. Upregulation of BDNF in descending pain modulating areas of the rostral ventromedial medulla (RVM) have been reported in a rat model of CIBP [59] suggesting that BDNF may also play a role in CIBP, yet the clinical evidence of whether anti- NGF or anti-BDNF can attenuate CIBP are unknown.…”

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

“…Microinjections were performed with a 0.5‐μl Hamilton syringe with a 32‐gauge needle to deliver 0.5 μl of solution (drug or vehicle) slowly over a 5‐min period. Five minutes after completion of the injection, the needle was withdrawn, after which the incision was sutured (Liu et al, ).…”

“…Controls underwent identical procedures with injection of 0.5 μl 0.2% DMSO in sterile 0.9% NS. Doses employed were those described previously (Wei et al, ; Roberts et al, ; Liu et al, ; Ren et al, ) and from the results of our preliminary experiments. The injection site was subsequently verified histologically (Fig.…”

“…It has been reported that activated glial cells and phosphorylation of glial p38 also occur in the RVM supraspinal center during inflammatory pain, neuropathic pain, or bone cancer pain (Wei et al, ; Roberts et al, ; Liu et al, ). Whether supraspinal glial activation and interactions with p38 MAPK signaling pathways in PAG circuitry constitute a valid mechanism underlying descending facilitation in the constriction nerve injury (CCI) model remains to be determined.…”