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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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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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.
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Dorsal horn N-methyl-D-aspartate (NMDA) receptors contribute significantly to spinal nociceptive processing through an effect postsynaptic to non-primary glutamatergic axons, and perhaps presynaptic to the primary afferent terminals. The present study sought to examine the regulatory effects of NMDA receptors on primary afferent release of substance P (SP), as measured by neurokinin 1 receptor (NK1r) internalization in the spinal dorsal horn of rats. The effects of intrathecal NMDA alone or in combination with D-serine (a glycine site agonist) were initially examined on basal levels of NK1r internalization. ⋯ In subsequent in vitro experiments, perfusion of NMDA in spinal cord slice preparations did not evoke basal release of SP or calcitonin gene-related peptide (CGRP). Likewise, perfusion of NMDA did not enhance capsaicin-evoked release of the two peptides. These results suggest that presynaptic NMDA receptors in the spinal cord play little if any role on the primary afferent release of SP.