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Central Mechanisms Mediating Thrombospondin-4-induced Pain States.

ABSTRACT: Peripheral nerve injury induces increased expression of thrombospondin-4 (TSP4) in spinal cord and dorsal root ganglia that contributes to neuropathic pain states through unknown mechanisms. Here, we test the hypothesis that TSP4 activates its receptor, the voltage-gated calcium channel Cav?2?1 subunit (Cav?2?1), on sensory afferent terminals in dorsal spinal cord to promote excitatory synaptogenesis and central sensitization that contribute to neuropathic pain states. We show that there is a direct molecular interaction between TSP4 and Cav?2?1 in the spinal cord in vivo and that TSP4/Cav?2?1-dependent processes lead to increased behavioral sensitivities to stimuli. In dorsal spinal cord, TSP4/Cav?2?1-dependent processes lead to increased frequency of miniature and amplitude of evoked excitatory post-synaptic currents in second-order neurons as well as increased VGlut2- and PSD95-positive puncta, indicative of increased excitatory synapses. Blockade of TSP4/Cav?2?1-dependent processes with Cav?2?1 ligand gabapentin or genetic Cav?2?1 knockdown blocks TSP4 induced nociception and its pathological correlates. Conversely, TSP4 antibodies or genetic ablation blocks nociception and changes in synaptic transmission in mice overexpressing Cav?2?1 Importantly, TSP4/Cav?2?1-dependent processes also lead to similar behavioral and pathological changes in a neuropathic pain model of peripheral nerve injury. Thus, a TSP4/Cav?2?1-dependent pathway activated by TSP4 or peripheral nerve injury promotes exaggerated presynaptic excitatory input and evoked sensory neuron hyperexcitability and excitatory synaptogenesis, which together lead to central sensitization and pain state development.

SUBMITTER: Park J

PROVIDER: S-EPMC4933243 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Central Mechanisms Mediating Thrombospondin-4-induced Pain States.

Park John J Yu Yanhui Peter YP Zhou Chun-Yi CY Li Kang-Wu KW Wang Dongqing D Chang Eric E Kim Doo-Sik DS Vo Benjamin B Zhang Xia X Gong Nian N Sharp Kelli K Steward Oswald O Vitko Iuliia I Perez-Reyes Edward E Eroglu Cagla C Barres Ben B Zaucke Frank F Feng Guoping G Luo Z David ZD

The Journal of biological chemistry 20160419 25

Peripheral nerve injury induces increased expression of thrombospondin-4 (TSP4) in spinal cord and dorsal root ganglia that contributes to neuropathic pain states through unknown mechanisms. Here, we test the hypothesis that TSP4 activates its receptor, the voltage-gated calcium channel Cavα2δ1 subunit (Cavα2δ1), on sensory afferent terminals in dorsal spinal cord to promote excitatory synaptogenesis and central sensitization that contribute to neuropathic pain states. We show that there is a di ...[more]

PMID: 27129212

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Project description:We evaluated the mechanism by which high-molecular-weight hyaluronan (HMWH) attenuates nociceptor sensitization, in the setting of inflammation. HMWH attenuated mechanical hyperalgesia induced by the inflammatory mediator prostaglandin E2 (PGE2) in male and female rats. Intrathecal administration of an oligodeoxynucleotide antisense (AS-ODN) to mRNA for cluster of differentiation 44 (CD44), the cognate hyaluronan receptor, and intradermal administration of A5G27, a CD44 receptor antagonist, both attenuated antihyperalgesia induced by HMWH. In male rats, HMWH also signals via Toll-like receptor 4 (TLR4), and AS-ODN for TLR4 mRNA administered intrathecally, attenuated HMWH-induced antihyperalgesia. Since HMWH signaling is dependent on CD44 clustering in lipid rafts, we pretreated animals with methyl-?-cyclodextrin (M?CD), which disrupts lipid rafts. M?CD markedly attenuated HMWH-induced antihyperalgesia. Inhibitors for components of intracellular signaling pathways activated by CD44, including phospholipase C and phosphoinositide 3-kinase (PI3K), also attenuated HMWH-induced antihyperalgesia. Furthermore, in vitro application of HMWH attenuated PGE2-induced sensitization of tetrodotoxin-resistant sodium current, in small-diameter dorsal root ganglion neurons, an effect that was attenuated by a PI3K inhibitor. Our results indicate a central role of CD44 signaling in HMWH-induced antihyperalgesia and suggest novel therapeutic targets, downstream of CD44, for the treatment of pain generated by nociceptor sensitization.SIGNIFICANCE STATEMENT High-molecular-weight-hyaluronan (HMWH) is used to treat osteoarthritis and other pain syndromes. In this study we demonstrate that attenuation of inflammatory hyperalgesia by HMWH is mediated by its action at cluster of differentiation 44 (CD44) and activation of its downstream signaling pathways, including RhoGTPases (RhoA and Rac1), phospholipases (phospholipases C? and C?1), and phosphoinositide 3-kinase, in nociceptors. These findings contribute to our understanding of the antihyperalgesic effect of HMWH and support the hypothesis that CD44 and its downstream signaling pathways represent novel therapeutic targets for the treatment of inflammatory pain.

Project description:PURPOSE:This is a comprehensive review of the current literature on central neuropathic pain mechanisms that is secondary to spinal cord injury. It reviews recent and seminal findings on the pathophysiology, diagnosis, and treatment and compares treatment options and recommendations. RECENT FINDINGS:Neuropathic pain (NP) is a common complication of spinal cord injury (SCI). Chronicity of NP is attributed to increased abundance of inflammatory mediators and ion channel dysfunction leading to afferent nerve sensitization; nerve damage and nerve-glia cross talk have also been implicated. Conventional treatment is medical and has had limited success. Recent studies have made headway in identifying novel biomarkers, including microRNA and psychosocial attributes that can predict progress from SCI to chronic NP (CNP). Recent advances have provided evidence of efficacy for two promising drugs. Baclofen was able to provide good, long-lasting pain relief. Ziconotide, a voltage-gated calcium channel blocker, was studied in a small trial and was able to provide good analgesia in most participants. However, several participants had to be withdrawn because of worrisome creatine phosphokinase (CPK) elevations, and further studies are required to define its safety profile. Non-medical interventions include brain sensitization and biofeedback techniques. These methods have recently had encouraging results, albeit preliminary. Case reports of non-conventional techniques, such as hypnosis, were also reported. CNP is a common complication of SCI and is a prevalent disorder with significant morbidity and disability. Conventional medical treatment is limited in efficacy. Recent studies identified baclofen and ziconotide as possible new therapies, alongside non-medical interventions. Further research into the pathophysiology is required to identify further therapy candidates. A multidisciplinary approach, including psychosocial support, medical and non-medical interventions, is likely needed to achieve therapeutic effects in this difficult to treat syndrome.

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Central Mechanisms Mediating Thrombospondin-4-induced Pain States.

Publications

Central Mechanisms Mediating Thrombospondin-4-induced Pain States.

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