Resolving TRPV1- and TNF- -Mediated Spinal Cord Synaptic Plasticity and Inflammatory Pain with Neuroprotectin D1

Sensory Plasticity Laboratory, Pain Research Center, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 10/2011; 31(42):15072-85. DOI: 10.1523/JNEUROSCI.2443-11.2011
Source: PubMed


Mechanisms of inflammatory pain are not fully understood. We investigated the role of TRPV1 (transient receptor potential subtype V1) and TNF-α, two critical mediators for inflammatory pain, in regulating spinal cord synaptic transmission. We found in mice lacking Trpv1 the frequency but not the amplitude of spontaneous EPSCs (sEPSCs) in lamina II neurons of spinal cord slices is reduced. Further, C-fiber-induced spinal long-term potentiation (LTP) in vivo is abolished in Trpv1 knock-out mice. TNF-α also increases sEPSC frequency but not amplitude in spinal outer lamina II (lamina IIo) neurons, and this increase is abolished in Trpv1 knock-out mice. Single-cell PCR analysis revealed that TNF-α-responding neurons in lamina IIo are exclusively excitatory (vGluT2(+)) neurons. Notably, neuroprotectin-1 (NPD1), an anti-inflammatory lipid mediator derived from ω-3 polyunsaturated fatty acid (docosahexaenoic acid), blocks TNF-α- and capsaicin-evoked sEPSC frequency increases but has no effect on basal synaptic transmission. Strikingly, NPD1 potently inhibits capsaicin-induced TRPV1 current (IC(50) = 0.4 nm) in dissociated dorsal root ganglion neurons, and this IC(50) is ≈ 500 times lower than that of AMG9810, a commonly used TRPV1 antagonist. NPD1 inhibition of TRPV1 is mediated by GPCRs, since the effects were blocked by pertussis toxin. In contrast, NPD1 had no effect on mustard oil-induced TRPA1 currents. Spinal injection of NPD1, at very low doses (0.1-10 ng), blocks spinal LTP and reduces TRPV1-dependent inflammatory pain, without affecting baseline pain. NPD1 also reduces TRPV1-independent but TNF-α-dependent pain hypersensitivity. Our findings demonstrate a novel role of NPD1 in regulating TRPV1/TNF-α-mediated spinal synaptic plasticity and identify NPD1 as a novel analgesic for treating inflammatory pain.

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    • "Previously, we and others have reported that sensory information processing in the spinal dorsal horn appears to undergo significant plastic changes e.g. long-term potentiation (LTP) in synaptic efficacy following peripheral nerve injury or inflammation (Park et al., 2011; Sandkuhler and Liu, 1998; Xing et al., 2007; Yang et al., 2014), which is well accepted as the underlying mechanisms of central sensitization and post-injury pain hypersensitivity (Ji et al., 2003; Latremoliere and Woolf, 2009; Sandkuhler, 2007; Woolf, 2011). Moreover, we have previously discovered that activation of spinal GluN2B-containing N-methyl-D-aspartate (GluN2B-NMDA) receptors is required for the induction of dorsal horn LTP at C-fiber synapses after nerve injury, implying GluN2B-dependent LTP in the spinal dorsal horn plays a crucial role in the development of long-lasting spinal neurons hyperexcitability (i.e. "
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    ABSTRACT: The pathogenic mechanisms underlying neuropathic pain still remain largely unknown. In this study, we investigated whether spinal BDNF contributes to dorsal horn LTP induction and neuropathic pain development by activation of GluN2B-NMDA receptors via Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) phosphorylation in rats following spinal nerve ligation (SNL). We first demonstrated that spinal BDNF participates in the development of long-lasting hyperexcitability of dorsal horn WDR neurons (i.e. central sensitization) as well as pain allodynia in both intact and SNL rats. Second, we revealed that BDNF induces spinal LTP at C-fiber synapses via functional up-regulation of GluN2B-NMDA receptors in the spinal dorsal horn, and this BDNF-mediated LTP-like state is responsible for the occlusion of spinal LTP elicited by subsequent high-frequency electrical stimulation (HFS) of the sciatic nerve in SNL rats. Finally, we validated that BDNF-evoked SHP2 phosphorylation is required for subsequent GluN2B-NMDA receptors up-regulation and spinal LTP induction, and also for pain allodynia development. Blockade of SHP2 phosphorylation in the spinal dorsal horn using a potent SHP2 protein tyrosine phosphatase inhibitor NSC-87877, or knockdown of spinal SHP2 by intrathecal delivery of SHP2 siRNA, not only prevents BDNF-mediated GluN2B-NMDA receptors activation as well as spinal LTP induction and pain allodynia elicitation in intact rats, but also reduces the SNL-evoked GluN2B-NMDA receptors up-regulation and spinal LTP occlusion, and ultimately alleviates pain allodynia in neuropathic rats. Taken together, these results suggest that the BDNF/SHP2/GluN2B-NMDA signaling cascade plays a vital role in the development of central sensitization and neuropathic pain after peripheral nerve injury. Copyright © 2014 Elsevier Inc. All rights reserved.
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    • "A slice was then transferred into a recording chamber and perfused with oxygenated recording solution at 3 ml/min at room temperature. The recording solution (Mg 2+ free) was identical to the incubation solution except for (in mM): NaCl 127, CaCl 2 2.4, MgSO 4 0 and sucrose 0. The whole-cell patch-clamp recordings were made from lamina IIo neurons in voltage-clamp mode as we previously reported (Park et al., 2011). Under a dissecting microscope with transmitted illumination, the substantia gelatinosa (lamina II) is clearly visible as a relatively translucent band across the dorsal horn. "
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    • "Along these lines, RvD1 (100 ng/kg) decreases TNBS-induced mechanical allodynia and blocked cytokine production in spinal dorsal horn (Quan-Xin et al. 2012), and RvD2 (0.01– 1 ng) prevents formalin-induced pain. As part of the molecular mechanisms, RvD2, RvE1, and RvD1 differentially regulated transient receptor potential (TRP) channels (Park et al. 2011). AT-RvD1 significantly reverses the thermal hypersensitivity, and knockdown of epidermal TRPV3 blunts these antinociceptive actions (Bang et al. 2012). "
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