TLQP-21 and C3R, a novel receptior/ligand interaction in neuropathic pain

  • Taylor, Bradley (PI)

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Peripheral neuropathic pain results from maladaptive changes in the central nervous system that are initiated by abnormal activity of injured sensory neurons. Increasing evidence indicates that neuroplasticity in the spinal cord depends on glial-neuronal interactions. In neuropathic pain, microglia, the resident immune cells of the central nervous system, play a critical role in both the development and maintenance of hypersensitivity. Several mediators, including chemokines and ATP, have been identified as important contributors to microglial activation following nerve injury. However, the injury-induced signals from sensory neurons that initiate glial activation, and the transition from acute to chronic pain, are not fully understood. Moreover, although it is known that ATP signaling through microglial purinergic receptors is required for the release of mediators that modify the excitability of dorsal horn neurons, the source of extracellular ATP has not been defined. Our published and preliminary data indicate that peptides derived from the neurosecretory protein VGF (non-acronymic) may function as sensory neuron signals that initiate microglial activation after nerve injury and participate in spinal neuroplasticity. The proposed studies will characterize the spinal signaling mechanisms of the VGF-derived peptide TLQP-21 and their contribution to the development and maintenance of neuropathic pain. The mechanistic understanding acquired will advance our search for new therapeutic targets for the treatment of neuropathic pain. Our long-term research goal is to delineate the role of VGF-derived neuropeptides in conditions of chronic pain. VGF is rapidly and robustly upregulated in sensory neurons at the onset of nerve injury and remains upregulated for the duration of the behavioral hypersensitivity, indicating that VGF peptides may participate both in the initiation of neuropathic pain and in its maintenance. The objective of this application is to define the role of the VGF-derived peptide TLQP-21 in mechanisms underlying nerve injury-induced hypersensitivity. Our preliminary data demonstrate that immunoneutralization of endogenous TLQP-21 attenuates the development of nerve injury-induced hypersensitivity as well as established hypersensitivity. Recently, TLQP-21 was shown to bind and activate the complement 3a receptor C3aR1. Furthermore, C3aR1 activation in monocytes has been implicated in release of cytokines and ATP. Although expression of C3aR1 in spinal cord has been reported, the cellular localization of this receptor in dorsal horn has not been characterized. The central hypothesis of this proposal is that TLQP-21 activation of microglial C3aR1 participates in mechanisms of spinal neuroplasticity during the development and maintenance of neuropathic pain. Specific Aim 1: Determine whether TLQP-21 contributes to neuropathic pain through activation of C3aR1. We hypothesize that the spinal effects of TLQP-21 are mediated by C3aR1, which is involved in the development and maintenance of nerve injury-induced hypersensitivity. The proposed studies will (1) characterize pharmacologically the ligand-receptor relationship of TLQP-21 and C3aR1 in spinal cord, (2) determine whether the spinal effects of TLQP-21 are dependent on C3aR1 activation, using behavioral and electrophysiological approaches, and (3) determine whether genetic ablation, siRNA-mediated knockdown, and pharmacological inhibition of C3aR1 attenuate nerve injury-induced hypersensitivity. Specific Aim 2: Determine whether microglial TLQP-21/C3aR1 signaling contributes to spinal neuroplasticity under conditions of neuropathic pain. We hypothesize that enhanced microglial TLQP-21/C3aR1 signaling after nerve injury potentiates the excitability of dorsal horn neurons. These studies will examine the effects of nerve injury on (1) the spinal localization of C3aR1 and binding of TLQP-21 to microglial C3aR1 in dorsal horn, (2) TLQP-21 evoked Ca2+ transients in spinal cord slices, and (3) TLQP-21 modulation of neuronal activity in dorsal horn using in vivo extracellular recording. Specific Aim 3: Determine whether TLQP-21 and C3aR1 modulate glial signaling under conditions of neuropathic pain. We hypothesize that TLQP-21 activation of glial C3aR1 contributes to mechanisms of hypersensitivity through ERK-dependent stimulation of glial ATP release. These studies will determine 1) whether TLQP-21 and C3aR1 modulate glial activation after nerve injury, and (2) whether TLQP-21 mediates glial ATP release in a C3aR-dependent manner. At the completion of these studies we will have determined the relationship of TLQP-21 to C3aR1 and their role in the development and maintenance of chronic pain. Such information will have a significant impact because the TLQP-21/C3aR1 system has the potential to provide new therapeutic approaches for reducing pain. The knowledge acquired from this research will greatly advance the field of chronic pain and may extend to other therapeutic areas related to neuroplasticity.
Effective start/end date6/1/143/31/18


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