Neuroscience
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Injuries to the cauda equina/conus medullaris portion of the spinal cord can result in motor, sensory, and autonomic dysfunction, and neuropathic pain. In rats, unilateral avulsion of the motor efferents from the lumbosacral spinal cord results in at-level allodynia, along with a corresponding glial and inflammatory response in the dorsal horn of the spinal cord segments immediately rostral to the lesion. Here, we investigated the fate of intramedullary primary sensory projections following a motor efferent lesion. ⋯ These results show for the first time that a lesion restricted to motor roots can induce the degeneration of intramedullary sensory afferents. Importantly, reimplantation of the lesioned motor roots ameliorated sensory axon degeneration. These data further support the therapeutic potential for reimplantation of avulsed ventral roots following trauma to the cauda equina/conus medullaris.
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Mutations in leucine-rich repeat kinase 2 (LRRK2) constitute the most common known cause of Parkinson's disease (PD), accounting for both familial and sporadic forms of the disease. We analyzed the tempo-spatial activity of leucine-rich repeat kinase 1 (LRRK1) and LRRK2 at the cellular level in human and rat tissues including development and aging. Lrrk2 mRNA is expressed in adult rat striatum, hippocampus, cerebral cortex, sensory and sympathetic ganglia, lung, spleen and kidney. ⋯ Transcription of both genes is also seen in the young human thymus and LRRK2 is active in tubular parts of the adult human kidney. Our findings suggest that the two paralogous genes have partly complementary expression patterns in the brain, as well as in certain peripheral organs including lymphatic tissues. While the strong presence of Lrrk2 message in striatum is intriguing in relation to PD, the many other neuronal and non-neuronal sites of Lrrk2 activity also needs to be taken into account in deciphering possible pathogenic pathways.
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Lysophosphatidic acid receptor (LPA(1)) signaling initiates neuropathic pain and several pathological events in a partial sciatic nerve injury model. Recently, we reported that lysophosphatidic acid (LPA) induces neuropathic pain as well as demyelination and pain-related protein expression changes via LPA(1) receptor signaling. Lysophosphatidylcholine (LPC), also known as lysolecithin, which is hydrolyzed by autotaxin/ATX into LPA, induces similar plastic changes. ⋯ On the other hand, LPC-induced mechanical allodynia and thermal hyperalgesia were completely abolished in mice lacking an LPA(1) receptor gene. Furthermore, the LPC-induced response was also significantly, but partially reduced in heterozygous mutant mice for the ATX gene. These findings suggest that intrathecally-injected LPC is converted to LPA by ATX, and this LPA activates the LPA(1) receptor to initiate neuropathic pain.
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Ankyrin-repeat transient receptor potential 1 (TRPA1) is a member of the transient receptor potential (TRP) channel family and it is found in sensory neurons. In the present study, we found that TRPA1 receptor activation with allyl isothiocyanate or cinnamaldehyde caused dose-dependent spontaneous nociception when injected into the mouse hind paw. Very similar results were obtained when stimulating transient receptor potential vanilloid 1 (TRPV1) receptors with capsaicin. ⋯ The selective NK(1) receptor antagonist N(2)-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl) carbony-1-L-prolyl]-N-methyl-N-phenylmethyl-3-2-(2-naphtyl)-L-alaninamide (10 nmol/paw) reduced either capsaicin- or allyl isothiocyanate-induced nociception. Collectively, the present findings demonstrate that the TRPA1 agonist allyl isothiocyanate produces a consistent nociceptive response when injected into the mouse paw, an effect that seems to be mediated via activation of TRPA1 receptor and dependent on the capsaicin-sensitive fibers, release of histamine by mast cells and participation of tachykinins. Thus, the TRPA1 receptor has an apparently relevant role in nociceptive processes and the selective TRPA1 antagonist might possess a potential antinociceptive property.
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Cation chloride co-transporters are important determinants for the efficacy of inhibitory neurotransmission in the spinal cord and alterations in their expression levels contribute to allodynia and hyperalgesia associated with neuropathy. However, it remains unknown whether these co-transporters contribute to chronic inflammatory pain. We investigated the expression of potassium-chloride co-transporter 2 (KCC2) and sodium-potassium-chloride co-transporter 1 (NKCC1) in the rat spinal cord after peripheral inflammation induced by complete Freund's adjuvant (CFA) injection. ⋯ Moreover, intrathecal injection of KCC2 antisense oligodeoxynucleotides into naïve rats reduced KCC2 expression in the spinal cord, leading to behavioral hypersensitivity similar to the hyperalgesia induced by peripheral inflammation. Taken together, these results indicate that peripheral inflammation induces downregulation of KCC2 in the dorsal horn of the spinal cord, which may in turn facilitate the development and/or maintenance of chronic inflammatory pain. The data also support the notion that disinhibition in the spinal cord is a general feature of inflammatory and neuropathic pain conditions, and suggest new therapeutic intervention.