Articles: hyperalgesia.
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Neuroscience letters · Sep 2011
Up-regulation of spinal glutamate transporters contributes to anti-hypersensitive effects of valproate in rats after peripheral nerve injury.
Valproate produces analgesia in animals and humans, however, its mechanisms of action are yet unknown. The present study examined effects of repeated administration of valproate on behavioral hypersensitivity and expression of glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter (GLAST) in the spinal dorsal horn in rats after L5-L6 spinal nerve ligation (SNL). ⋯ This analgesia from valproate was blocked by the selective GLT-1 blocker dihydrokainic acid (DHK). These data suggest that valproate restores down-regulated expression of glutamate transporters in the spinal cord to presumably reduce glutamate signaling and to reduce hypersensitivity after nerve injury, and that combination of valproate with riluzole produces enhanced analgesia which relies on the spinal glutamate transporters.
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Recent studies indicate that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT(3) receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT(3) receptor and its contribution to facilitation of pain remain unclear. In the present study, activation of spinal 5-HT(3) receptor by intrathecal injection of a selective 5-HT(3) receptor agonist, SR57227, induced spinal glial hyperactivity, neuronal hyperexcitability, and pain hypersensitivity in rats. ⋯ Enhanced expression of spinal CD11b and GFAP after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference. Thus, these findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neuron and glia.
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Comparative Study
Activation of spinal extracellular signal-regulated kinases (ERK) 1/2 is associated with the development of visceral hyperalgesia of the bladder.
Activation of extracellular signal-regulated kinases (ERK) 1/2 in dorsal horn neurons is important for the development of somatic hypersensitivity and spinal central sensitization after peripheral inflammation. However, data regarding the roles of spinal ERK1/2 in the development of visceral hyperalgesia are sparse. Here we studied the activation of ERK1/2 in the lumbosacral spinal cord after innocuous and noxious distention of the inflamed (cyclophosphamide-treated) and noninflamed urinary bladder in mice. ⋯ Functional blockade of spinal ERK1/2 activity via intrathecal administration of the upstream MEK inhibitor U0126 attenuated distention-evoked bladder nociception and caused a significant downward shift of the VMR stimulus-response curve. In summary, we have provided functional and immunohistochemical evidence that activation of lumbosacral spinal ERK1/2 is associated with the development of primary visceral (bladder) hyperalgesia. Our results suggest that aberrant processing of visceral nociceptive information at the level of the lumbosacral spinal cord via activation of ERK1/2 signaling may contribute to chronic bladder pain in the context of inflammation.
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Comparative Study
Eugenol reverses mechanical allodynia after peripheral nerve injury by inhibiting hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.
Mechanical allodynia is a common symptom found in neuropathic patients. Hyperpolarization-activated cyclic nucleotide-gated channels and their current, I(h), have been suggested to play an important role in neuropathic pain, especially in mechanical allodynia and spontaneous pain, by involvement in spontaneous ectopic discharges after peripheral nerve injury. Thus, I(h) blockers may hold therapeutic potential for the intervention of mechanical allodynia under diverse neuropathic conditions. ⋯ Eugenol-induced I(h) inhibition was not mediated by G(i/o)-protein activation, but was gradually diminished by an increase in intracellular cAMP concentration. Eugenol also inhibited I(h) from injured TG neurons which were identified by retrograde labeling with DiI and reversed mechanical allodynia in the orofacial area after chronic constriction injury of infraorbital nerve. We propose that eugenol could be potentially useful for reversing mechanical allodynia in neuropathic pain patients.
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We aim to determine the effects of Botulinum toxin type A (BTX-A) on neuropathic pain behavior and the expression of P2X(3) receptor in dorsal root ganglion (DRG) in rats with neuropathic pain induced by L5 ventral root transection (L5 VRT). ⋯ L5 VRT led to over-expression of P2X(3) receptors in the L5 DRG and bilateral mechanical allodynia in rats. Subcutaneous injection of BTX-A significantly reversed the neuropathic pain behavior and the over-expression of P2X(3) receptor in nociceptive neurons. These data not only show over-expression of purinergic receptors in the VRT model of neuropathic pain but also reveal a novel mechanism of botulinum toxin action on nociceptive neurons.