BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain

Abstract

Neuropathic pain that occurs after peripheral nerve injury depends on the hyperexcitability of neurons in the dorsal horn of the spinal cord. Spinal microglia stimulated by ATP contribute to tactile allodynia, a highly debilitating symptom of pain induced by nerve injury. Signalling between microglia and neurons is therefore an essential link in neuropathic pain transmission, but how this signalling occurs is unknown. Here we show that ATP-stimulated microglia cause a depolarizing shift in the anion reversal potential (E(anion)) in spinal lamina I neurons. This shift inverts the polarity of currents activated by GABA (gamma-amino butyric acid), as has been shown to occur after peripheral nerve injury. Applying brain-derived neurotrophic factor (BDNF) mimics the alteration in E(anion). Blocking signalling between BDNF and the receptor TrkB reverses the allodynia and the E(anion) shift that follows both nerve injury and administration of ATP-stimulated microglia. ATP stimulation evokes the release of BDNF from microglia. Preventing BDNF release from microglia by pretreating them with interfering RNA directed against BDNF before ATP stimulation also inhibits the effects of these cells on the withdrawal threshold and E(anion). Our results show that ATP-stimulated microglia signal to lamina I neurons, causing a collapse of their transmembrane anion gradient, and that BDNF is a crucial signalling molecule between microglia and neurons. Blocking this microglia-neuron signalling pathway may represent a therapeutic strategy for treating neuropathic pain.

Do glial cells control pain?

“…Interestingly, intrathecal injection of ATP-activated microglia in the spinal cord is sufficient to induce pain (Tsuda et al, 2003). Further studies indicate that ATP-activated microglia can enhance pain by producing the growth factor BDNF (Coull et al, 2005). BDNF can act on lamina I neurons in the spinal cord to remove GABA inhibition by altering chloride reverse potential (Coull et al, 2005).…”

“…Further studies indicate that ATP-activated microglia can enhance pain by producing the growth factor BDNF (Coull et al, 2005). BDNF can act on lamina I neurons in the spinal cord to remove GABA inhibition by altering chloride reverse potential (Coull et al, 2005). ATP may also activate P2X7 receptors in spinal microglia to enhance pain (Donnelly-Roberts et al, 2007;Inoue, 2006).…”

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

“…Either blocking or deleting these receptors results in decreased neuropathic pain (Tsuda et al, 2003;Verge et al, 2004;Zhuang et al, 2006b). Intrathecal injection of ATP-activated microglia induces mechanical allodynia (a nociceptive response to normally innocuous mechanical stimulation) that requires microglial production of BDNF (Tsuda et al, 2003;Coull et al, 2005). A non-specific microglial inhibitor minocycline prevents/delays pain development (Raghavendra et al, 2003;Ledeboer et al, 2005;Hua et al, 2005).…”

Dynamic regulation of the P2X4 receptor in alveolar macrophages by phagocytosis and classical activation

“…The case for P2X 4 R remains tentative, largely due to the absence of selective P2X 4 R antagonists and the complicating presence of P2X 7 R, which is generally co-expressed with P2X 4 R in macrophages and microglia [3]. P2X 4 R does not appear to couple to any of the same downstream signalling cascades as has been demonstrated for P2X 7 R but studies with P2X 4 R gene-deleted mice have revealed abrogation of tactile allodynia in animal models of inflammatory (formalin-induced) and neuropathic (nerve section) pain via yet-to-be identified alterations in microglial functions [12][13][14].P2X 4 R expression at the plasma membrane of neurones and macrophages is subject to tight regulation by rapid recycling via the AP2/clathrin-dependent endocytic pathway [15,16]. Qureshi et al [17] have recently found that phagocytosis of zymosan or latex beads by mouse peritoneal macrophages lead to accumulation of P2X 4 R at the phagosome membrane; when lysosomal exocytosis was induced by the calcium ionophore, ionomycin, a significant increase in the plasma membrane surface expression of P2X 4 R occurred with concomitant increase in the ATP-evoked currents.…”

“…The case for P2X 4 R remains tentative, largely due to the absence of selective P2X 4 R antagonists and the complicating presence of P2X 7 R, which is generally co-expressed with P2X 4 R in macrophages and microglia [3]. P2X 4 R does not appear to couple to any of the same downstream signalling cascades as has been demonstrated for P2X 7 R but studies with P2X 4 R gene-deleted mice have revealed abrogation of tactile allodynia in animal models of inflammatory (formalin-induced) and neuropathic (nerve section) pain via yet-to-be identified alterations in microglial functions [12][13][14].…”