The journal of pain : official journal of the American Pain Society
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The present study examined whether the histone deacetylase inhibitor valproate prevents downregulation of glutamate transporters in the primary cultured astrocytes and in the spinal cord after L5-L6 spinal nerve ligation (SNL) and whether this action of valproate on spinal glutamate transporters prevents spinal glutamate dysregulation and development of hypersensitivity after SNL. In cultured astrocytes, valproate prevented downregulation of glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter in a concentration-dependent manner. Repeated oral administration of valproate reduced the development of hypersensitivity and prevented the downregulation of spinal GLT-1 and glutamate-aspartate transporter expression in rats after SNL, but did not affect mechanical nociception and expression of those transporters in normal rats. Valproate's effects on hypersensitivity and spinal GLT-1 expression in SNL rats were blocked by intrathecal administration of the selective GLT-1 blocker dihydrokainic acid or the GLT-1 selective small interfering RNA (siRNA). Extracellular glutamate concentration in the spinal cord, measured by microdialysis, was increased in animals with SNL or after GLT-1 selective siRNA treatment, and valproate prevented the SNL-induced glutamate increase. These results suggest that valproate reduces the development of chronic pain after nerve injury in part by preventing downregulation of glutamate transporters, especially GLT-1, to maintain normal extracellular glutamate concentrations in the spinal cord. ⋯ This study demonstrates that valproate prevents the downregulation of glutamate transporters in the spinal cord, which contributes in part to the development of chronic pain after nerve injury. Given clinical availability and established safety profiles, perioperative use of valproate should be tested to prevent chronic pain after surgery.
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Multiple brain areas involved in nociceptive, autonomic, and social-emotional processing are disproportionally changed in patients with complex regional pain syndrome (CRPS). Little empirical evidence is available involving social cognitive functioning in patients with chronic pain conditions. We investigated the ability of patients with CRPS to recognize the mental/emotional states of other people. Forty-three patients with CRPS and 30 healthy controls performed the Reading Mind in the Eyes Test, which consists of photos in which human eyes express various emotional and mental states. Neuropsychological tests, including the Wisconsin Card Sorting Test, the stop-signal test, and the reaction time test, were administered to evaluate other cognitive functions. Patients with CRPS were significantly less accurate at recognizing emotional states in other persons, but not on other cognitive tests, compared with control subjects. We found a significant association between the deficit in social-emotion recognition and the affective dimension of pain, whereas this deficit was not related to the sensory dimension of pain. Our findings suggest a disrupted ability to recognize others' mental/emotional states in patients with CRPS. ⋯ This article demonstrated a deficit in inferring mental/emotional states of others in patients with CRPS that was related to pain affect. Our study suggests that additional interventions directed toward reducing distressful affective pain may be helpful to restore social cognitive processing in patients with CRPS.
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Several recent studies have revealed that statins exert anti-inflammatory effects in addition to their lipid-lowering property in vivo and in vitro. Recently, statins were shown to alleviate pain associated trauma in a neuropathic pain model. The aim of the present study was to investigate the underlying mechanisms of analgesia caused by the lipophilic statin simvastatin in an animal model of formalin-induced pain in the rat. Intrathecal pretreatment with simvastatin significantly attenuated the second phase of the acute nociceptive response to formalin injection, and daily administration of simvastatin for 7 days inhibited the long-term mechanical hyperalgesia caused by formalin injection. Spinal microglial activation (detected by Iba-1 and CD11 b immunohistochemistry and Western blot), and phosphorylated-p38 mitogen-activated protein kinase (detected by immunohistochemistry and Western blot) were significantly inhibited by simvastatin treatment at day 7 after formalin injection. In addition, peripheral formalin injection induced a significant increase in microglial RhoA activation (detected by membrane RhoA translocation ratio using Western blot) in the spinal cord. The spinal RhoA activation in microglia was reversed by simvastatin treatment. These findings suggest that simvastatin attenuates formalin-induced nociceptive behaviors, at least in part, by inhibiting microglial RhoA and p38 mitogen-activated protein kinase activation. ⋯ Our novel findings indicated that simvastatin attenuated formalin-induced nociceptive responses by inhibiting microglial RhoA and p38 mitogen-activated protein kinase activation. Inactivation of RhoA-p38 signaling pathway may be a pharmacologic target for treating microglia-directed central nervous system inflammation and chronic pain conditions.
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Levetiracetam is a novel anticonvulsant with antihyperalgesic efficacy in inflammatory pain. Nonsteroidal analgesics and caffeine, as analgesic adjuvant, are widely used against inflammatory pain. This study characterized the manner in which levetiracetam interacts with analgesics (ibuprofen, celecoxib, and paracetamol) and caffeine to suppress hyperalgesia in a model of localized inflammation. Rat paw inflammation was induced by intraplantar carrageenan (.1 mL, 1%). Hyperalgesia and antihyperalgesic effects of levetiracetam (orally), analgesics (orally), and caffeine (intraperitoneally) alone and 2-drug combinations of levetiracetam with analgesics or caffeine were examined by a modified paw pressure test. The type of interaction between components was determined by isobolographic analysis or by analysis of the log dose-response curves for drug combination and drugs alone. Levetiracetam (10-200 mg/kg), ibuprofen (12.5-100 mg/kg), celecoxib (3.75-30 mg/kg), paracetamol (50-200 mg/kg), caffeine (15-100 mg/kg), and 2-drug combinations of levetiracetam with analgesics/caffeine produced a significant, dose-dependent reduction of inflammatory hyperalgesia. Isobolographic analysis revealed that levetiracetam exerts a synergistic interaction with analgesics, with approximately 7-, 9-, and 11-fold reduction of doses of both drugs in combination of levetiracetam with paracetamol, celecoxib, and ibuprofen, respectively. Analysis of the log dose-response curves for levetiracetam (1-50 mg/kg) in the presence of caffeine (10 mg/kg) and levetiracetam applied alone also revealed a synergistic interaction. Levetiracetam's ED50 in the presence of caffeine was reduced approximately 11-fold. ⋯ The presented data suggest that 2-drug combinations of levetiracetam and nonsteroidal analgesics or caffeine could be useful in treatment of inflammatory pain. The efficacy and the adverse effects of those mixtures should be explored further in clinical settings.
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The activation of the adenosine monophosphate (AMP)-activated kinase (AMPK) has been associated with beneficial effects such as improvement of hyperglycemic states in diabetes as well as reduction of obesity and inflammatory processes. Recent studies provide evidence for a further role of AMPK in models of acute and neuropathic pain. In this study, we investigated the impact of AMPK on inflammatory nociception. Using 5-amino-1-β-d-ribofuranosyl-imidazole-4-carboxamide (AICAR) and metformin as AMPK activators, we observed anti-inflammatory and antinociceptive effects in 2 models of inflammatory nociception. The effects were similar to those observed with the standard analgesic ibuprofen. The mechanism appears to be based on regulation of the AMPKα2 subunit of the kinase because AMPKα2 knockout mice showed increased nociceptive responses that could not be reversed by the AMPK activators. On the molecular level, antinociceptive effects are at least partially mediated by reduced activation of different MAP-kinases in the spinal cord and a subsequent decrease in pain-relevant induction of c-fos, which constitutes a reliable marker of elevated activity in spinal cord neurons following peripheral noxious stimulation. In summary, our results indicate that activation of AMPKα2 might represent a novel therapeutic option for the treatment of inflammation-associated pain, providing analgesia with fewer unwanted side effects. ⋯ AMPK activation is associated with beneficial effects on diabetes and obesity. In addition, we have shown analgesic properties of pharmacologic AMPK activation in inflammatory nociception, indicating that AMPK might serve as a novel therapeutic target in pain with fewer unwanted side effects.