Neuroscience
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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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The present study examined the involvement of 5-HT in the ventrolateral orbital cortex (VLO) on descending antinociception and determined which subtypes of 5-HT receptors mediated this effect. This study focused on the effects of 5-HT microinjection in the VLO of lightly anesthetized male rats on the radiant heat-evoked tail flick (TF) reflex, as well as the influence of 5-HT(1A), 5-HT(2), 5-HT(3), and 5-HT(4) receptor subtype antagonists on the effect of 5-HT. Results showed that 5-HT microinjection (2, 5, 10 microg, in 0.5 microl) into the VLO depressed the TF reflex in a dose-dependent manner. ⋯ Microinjections of NAN-190, CPT and LY-278,584 alone into the VLO had no effect on the TF reflex. These results suggest that 5-HT(1A), 5-HT(2) and 5-HT(3), but not 5-HT(4) receptors, are involved in mediating 5-HT-induced antinociception in the VLO. According to different properties and distribution patterns of the 5-HT receptor subtypes on neurons, the possible mechanism of 5-HT activation of the VLO-periaqueductal gray (PAG) descending antinociceptive pathway is discussed.
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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.
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Experimental autoimmune neuritis (EAN) is the animal model of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) that is the most common subtype of Guillain-Barre syndrome (GBS). While neuropathic pain is a common symptom of GBS, its underlying mechanisms remain elusive. Central sensitization, particularly spinal glia (microglia and astrocytes) activation, is important for the initiation and maintenance of neuropathic pain. ⋯ Furthermore, a negative correlation between the density of P2X(4)R(+) cells in the lumbar dorsal horn with mean hind-paw withdrawal threshold in EAN rats was seen, indicating that P2X(4)R might contribute to EAN mechanical allodynia. Double staining revealed that almost all P2X(4)R(+) cells co-expressed CD68, a marker for reactive microglia, but not the astrocyte marker, glial fibrillary acidic protein (GFAP). Our data demonstrate that EAN induces mechanical allodynia and P2X(4)R expression in spinal microglia, suggesting that EAN is a good animal model for neuropathic pain in polyneuropathy and spinal microglia activation might participate in EAN-induced neuropathic pain.
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After recovery from acute muscle pain even minor subsequent muscle use can initiate recurrence of the same mechanical hyperalgesia months or years after the initial injury. We have recently developed a model of this chronic latent hyperalgesia in the rat. In this study, we have examined the possibility that interleukin-6 (IL-6), an inflammatory mediator produced during acute muscle inflammation, can mediate the production of this chronic latent hyperalgesic state in which subsequent exposure to inflammatory mediators produces a markedly prolonged mechanical hyperalgesia. ⋯ This ability of IL-6 to produce chronic latent hyperalgesia was prevented by intrathecal administration of antisense for gp130. Furthermore, gp130 antisense also prevented chronic latent hyperalgesia produced by i.m. injection of the inflammogen, carrageenan. These results identify a role for IL-6 in acute inflammatory muscle pain and as a potential target against which therapies might be directed to treat chronic muscle pain.