Spinal Astrocytic Activation Contributes to Mechanical Allodynia in a Rat Chemotherapy-Induced Neuropathic Pain Model

Abstract

Chemotherapy-induced neuropathic pain (CNP) is the major dose-limiting factor in cancer chemotherapy. However, the neural mechanisms underlying CNP remain enigmatic. Accumulating evidence implicates the involvement of spinal glia in some neuropathic pain models. In this study, using a vincristine-evoked CNP rat model with obvious mechanical allodynia, we found that spinal astrocyte rather than microglia was dramatically activated. The mechanical allodynia was dose-dependently attenuated by intrathecal administratration of L-α-aminoadipate (astrocytic specific inhibitor); whereas minocycline (microglial specific inhibitor) had no such effect, indicating that spinal astrocytic activation contributes to allodynia in CNP rat. Furthermore, oxidative stress mediated the development of spinal astrocytic activation, and activated astrocytes dramatically increased interleukin-1β expression which induced N-methyl-D-aspartic acid receptor (NMDAR) phosphorylation in spinal neurons to strengthen pain transmission. Taken together, our findings suggest that spinal activated astrocytes may be a crucial component of the pathophysiology of CNP and “Astrocyte-Cytokine-NMDAR-neuron” pathway may be one detailed neural mechanisms underlying CNP. Thus, inhibiting spinal astrocytic activation may represent a novel therapeutic strategy for treating CNP.

Exogenous induction of HO-1 alleviates vincristine-induced neuropathic pain by reducing spinal glial activation in mice

“…CoPP also inhibited microglial activation in the spinal cord after sciatic nerve injury-induced neuropathic pain (Hervera et al, 2012(Hervera et al, , 2013. Given the important role of spinal glial cells in neuropathic pain (Ji et al, 2013b;Zhang et al, 2012), these data support that the antinociceptive effect of HO-1 may, at least in part, be mediated through inhibition of glial activation in the spinal cord. We do not exclude the possibility that HO-1 may exert anti-nociceptive effect via modulation of neuronal nitric oxide synthase (NOS1) (Chu et al, 2005;Hervera et al, 2012) and cGMP (Komatsu et al, 2009;Nascimento and Branco, 2008) in spinal neurons.…”

“…However, the correlation of glial activation in the spinal cord with chemotherapyinduced pain is unclear. Some studies showed that spinal microglia was not activated in rats treated with vincristine or oxaliplatin (Ji et al, 2013b;Zhang et al, 2012;Zheng et al, 2011), but astrocytes were activated after vincristine injection (Ji et al, 2013b). However, Sweitzer et al showed that vincristine induced activation of microglia and astrocytes in the spinal cord in rats (Sweitzer et al, 2006).…”

“…Tissue inflammation and nerve injury induce glial cells (astrocytes and microglia) to be reactive, activate intracellular kinases (e.g., mitogen-activated protein kinases, MAPKs), and release a variety of inflammatory mediators (such as proinflammatory cytokines and chemokines), which may augment the nociceptive signals in the spinal cord (Gao and Ji, 2010a,b;Ji et al, 2013a;Scholz and Woolf, 2007). However, the activation of astrocytes and microglia in the spinal cord in chemotherapy-induced neuropathy is still debated (Ji et al, 2013b;Sweitzer et al, 2006;Zhang et al, 2012;Zheng et al, 2011). Whether HO-1 can regulate spinal glial activation, MAPK phosphorylation, and production of inflammatory mediators in chemotherapy-induced neuropathy remains to be investigated.…”

Involvement of p38 MAPK activation mediated through AT1 receptors on spinal astrocytes and neurons in angiotensin II- and III-induced nociceptive behavior in mice

“…The analgesic effects of these inhibitors following i.t. administration are shown to depend on the inhibition of spinal glial activation in neuropathic and inflammatory pain models (Ikeda et al, 2012;Ji et al, 2013). Microglia produces multiple cytokines, including interleukin-1β, interleukin-6 and tumor necrosis factor-α (for review, see Ref.…”

Stress-Induced Pain: A Target for the Development of Novel Therapeutics

“…Selective antagonists, applied into discrete brain or spinal regions, are antinociceptive in animal models of neuropathic pain. Specifically, MK-801 [(5S,10R)-(1)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate], an NMDA antagonist, decreased mechanical allodynia and reduced microglia activation in a model of SNL (Kim and Jeong, 2013), while both MK-801 and AP5 (2-amino-5-phosphonopentanoic acid) reversed mechanical allodynia induced by vincristine in a model of chemotherapy-induced neuropathic pain (Ji et al, 2013). When applied to stress-responsive brain regions, ionotropic glutamate receptor antagonists inhibit the HPA axis.…”