Articles: hyperalgesia.
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We investigated whether milnacipran, a serotonin-noradrenaline reuptake inhibitor, would have therapeutic effect on oxaliplatin-induced mechanical allodynia in mice. A single intraperitoneal injection of oxaliplatin (3 mg/kg) induced mechanical allodynia, which peaked on day 10 after injection and almost completely subsided by day 20. ⋯ Intrathecal injections of milnacipran (2.1-21 µg/site) also significantly and dose-dependently inhibited mechanical allodynia, but intracisternal and intracereboventricular injections at the same doses did not. The present results suggest that milnacipran is effective against oxaliplatin-induced mechanical allodynia and that the antiallodynic effect is mainly mediated by actions on the spinal cord.
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Brain research bulletin · Jan 2015
Nociceptive spinal cord neurons of laminae I-III exhibit oxidative stress damage during diabetic neuropathy which is prevented by early antioxidant treatment with epigallocatechin-gallate (EGCG).
Spinal cord neurons located in laminae I-III respond to nociceptive stimuli and participate in the transmission of painful information to the brain. In the present study we evaluated if nociceptive laminae I-III neurons are affected by oxidative stress damage in a model of diabetic neuropathic pain (DNP), the streptozotocin-induced diabetic rat (STZ rat). Additionally, we evaluated the effects of a preventive antioxidant treatment with epigallocatechin-gallate (EGCG) in nociceptive neuronal activation and behavioural signs of DNP. ⋯ Treatment with EGCG normalized the increase of the above mentioned parameters and ameliorated mechanical hypersensitivity. The present study shows that nociceptive neurons in spinal cord laminae I-III exhibit oxidative stress damage during diabetic neuropathy, which probably affects ascending pain transmission during DNP. The neurobiological mechanisms and translational perspectives of the beneficial effects of a preventive and sustained EGCG treatment in DNP need to be evaluated in the future.
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Following the resolution of a severe inflammatory injury in rodents, administration of mu-opioid receptor inverse agonists leads to reinstatement of pain hypersensitivity. The mechanisms underlying this form of latent pain sensitization (LS) likely contribute to the development of chronic pain, but LS has not yet been demonstrated in humans. Using a C57BL/6 mouse model of cutaneous mild heat injury (MHI) we demonstrated a dose-dependent reinstatement of pain sensitization, assessed as primary (P < 0.001) and secondary hyperalgesia (P < 0.001) by naloxone (0.3–10 mg/kg), 168 hrs after the induction of MHI. Forward-translating the dose data to a human MHI model (n = 12) we could show that LS does indeed occur after naloxone 2 mg/kg, 168 hrs after a MHI. Our previous unsuccessful efforts to demonstrate unmasking of LS in humans are thus likely explained by an insufficient naloxone dose (0.021 mg/kg). However, while LS was consistently demonstrated in 21/24 mice, LS was only seen in 4/12 subjects. This difference is likely due to selection bias since the C57BL/6 mouse strain exhibits markedly enhanced pain sensitivity in assays of acute thermal nociception. Future exploratory studies in humans should prioritize inclusion of “high-sensitizers” prone to develop LS and use post-surgical models to elucidate markers of vulnerability to chronic postsurgical pain.
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Rufinamide is a structurally novel, antiepileptic drug approved for the treatment of Lennox-Gastaut syndrome. Its mechanism of action involves inhibition of voltage-gated Na+ channels (VGSCs) with possible membrane-stabilizing effects. VGSCs play a significant role in the pathogenesis of neuropathic pain. ⋯ Rufinamide treatments significantly blocked the TTX-R Na+ channel activity as evident from significant reduction in I(Na) density and hyperpolarizing shift in activation and inactivation curves as compared to diabetic control. This suggests that rufinamide acts on TTX-R Na+ channels, reduces channel activity and attenuates nerve functional and behavioral parameters in diabetic rats. Altogether, these results indicate therapeutic potential of rufinamide in the treatment of diabetic neuropathy.
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Water immersion is widely used in physiotherapy and might relieve pain, probably by activating several distinct somatosensory modalities, including tactile, pressure, and thermal sensations. However, the endogenous mechanisms behind this effect remain poorly understood. This study examined whether warm water immersion therapy (WWIT) produces an antiallodynic effect in a model of localized inflammation and whether peripheral opioid, cannabinoid, and adenosine receptors are involved in this effect. ⋯ WWIT produced a significant time-dependent reduction of paw inflammatory allodynia but did not influence paw edema induced by CFA. Naloxone, caffeine, DPCPX, and AM630 injected in the right, but not in the left, hind paw significantly reversed the antiallodynic effect of WWIT. This is the first study to demonstrate the involvement of peripheral receptors in the antiallodynic effect of WWIT in a murine model of persistent inflammatory pain.