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Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2014)

Upregulation of the thrombospondin-4 (TSP4) or calcium channel alpha-2-delta-1 subunit (Cava2d1) in the dorsal spinal cord and dorsal root ganglia plays a causal role in neuropathic pain development through an unidentified mechanism. TSP4 blockade either by antibodies or inactivation of the TSP4 gene prevents development of chronic pain states. Intrathecal injection of TSP4 proteins into naive rats can cause dorsal horn neuron hyperexcitability and allodynia, which are blocked by the Cava2d1 ligand gabapentin. These findings suggest that TSP4 and Cava2d1 may interact together in mediating pain processing. Here, I show that TSP4 binding to Cava2d1 is detectable in the same immunocomplexes from rodent spinal cords and in solid-phase binding. SPOT Peptide array analysis and in vitro binding of TSP4 recombinant truncation proteins to Cava2d1 reveal multiple binding sites within the TSP4 Epidermal Growth Factor-like domains (EGF-like) and coil-coil domain. Functionally, lumbar intrathecal injection of EGF-like domain proteins is sufficient to induce behavioral hypersensitivity. Selective ablation of Cava2d1 from Nav1.8-positive sensory neurons abolishes EGF-like domain induced thermal hyperalgesia, but not tactile allodynia. A 15-mer TSP4 peptide from the EGF-like domains can block both Cava2d1- and TSP4-induced behavioral hypersensitivity, presumably by disrupting the interaction between TSP4 and Cava2d1. My data suggest that the EGF-like domains of TSP4 interact with Cava2d1 to induce chronic pain states in a modality specific manner. Emerging data also suggest that Cava2d1 and TSP4 interact to induce synapse formation. To determine if maladaptive changes in synapses correlate with neuropathic pain states in a nerve injury model with injury-induced upregulation of TSP4 and Cava2d1, I examined synapse numbers at ultrastructure level in superficial dorsal horn of rats after trigeminal nerve injury. I found a significant increase in both excitatory and inhibitory synapses within lamina I and II of the superficial dorsal horn, respectively, and a decrease in mean synaptic length, a marker for synapse strength, of inhibitory interneurons mainly in lamina I of the injury side. Together, it is likely that injury-induced TSP4/Cava2d1 contribute to the development of chronic pain states after nerve injury through a mechanism involving dysregulation of excitatory and inhibitory synapses in the superficial dorsal horn.

    Cover page: Mechanisms of Thrombospondin-4 in Pain Modulation
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2014)
    To investigate a potential mechanism underlying trigeminal nerve injury-induced orofacial hypersensitivity, we used a rat model of chronic constriction injury to the infraorbital nerve (CCI-ION) to study whether CCI-ION caused calcium channel α2δ1 (Cavα2δ1) protein dysregulation in trigeminal ganglia and associated spinal subnucleus caudalis and C1/C2 cervical dorsal spinal cord (Vc/C2). Furthermore, we studied whether this neuroplasticity contributed to spinal neuron sensitization and neuropathic pain states. CCI-ION caused orofacial hypersensitivity that correlated with Cavα2δ1 up-regulation in trigeminal ganglion neurons and Vc/C2. Blocking Cavα2δ1 with gabapentin, a ligand for the Cavα2δ1 proteins, or Cavα2δ1 antisense oligodeoxynucleotides led to a reversal of orofacial hypersensitivity, supporting an important role of Cavα2δ1 in orofacial pain processing. Importantly, increased Cavα2δ1 in Vc/C2 superficial dorsal horn was associated with increased excitatory synaptogenesis and increased frequency, but not the amplitude, of miniature excitatory postsynaptic currents in dorsal horn neurons that could be blocked by gabapentin. Thus, CCI-ION-induced Cavα2δ1 up-regulation may contribute to orofacial neuropathic pain states through abnormal excitatory synapse formation and enhanced presynaptic excitatory neurotransmitter release in Vc/C2.
      Cover page: Calcium channel α2δ1 proteins mediate trigeminal neuropathic pain states associated with aberrant excitatory synaptogenesis.
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2014)
      BACKGROUND: Current pain management is limited, in particular, with regard to chronic pain. In an attempt to discover novel analgesics, we combined the approach developed to characterize traditional Chinese medicine (TCM), as part of the herbalome project, with the reverse pharmacology approach aimed at discovering new endogenous transmitters and hormones. RESULTS: In a plant used for centuries for its analgesic properties, we identify a compound, dehydrocorybulbine (DHCB), that is effective at alleviating thermally induced acute pain. We synthesize DHCB and show that it displays moderate dopamine receptor antagonist activities. By using selective pharmacological compounds and dopamine receptor knockout (KO) mice, we show that DHCB antinociceptive effect is primarily due to its interaction with D2 receptors, at least at low doses. We further show that DHCB is effective against inflammatory pain and injury-induced neuropathic pain and furthermore causes no antinociceptive tolerance. CONCLUSIONS: Our study casts DHCB as a different type of analgesic compound and as a promising lead in pain management.
        Cover page: A novel analgesic isolated from a traditional Chinese medicine.
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