Articles: hyperalgesia.
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Oxaliplatin is an anticancer drug used for the treatment of advanced colorectal cancer, but it can also cause painful peripheral neuropathies. The pathophysiology of these neuropathies has not been yet fully elucidated, but may involve spinal N-methyl-D-aspartate (NMDA) receptors, particularly the NR2B subunit. As polyamines are positive modulators of NMDA-NR2B receptors and mainly originate from dietary intake, the modulation of polyamines intake could represent an interesting way to prevent/modulate neuropathic pain symptoms by opposing glutamate neurotransmission. ⋯ A polyamine deficient diet could represent a promising and valuable nutritional therapy to prevent oxaliplatin-induced acute pain hypersensitivity.
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Pyrroloquinoline quinone PQQ is a naturally occurring redox cofactor that acts as an essential nutrient, antioxidant, and redox modulator. PQQ has been demonstrated to oxidize the redox modulatory site of N-methyl-d-aspartic acid (NMDA) receptors. Such agents are known to be neuroprotective in experimental stroke models. ⋯ The repeated oral administration of PQQ (20 and 40mg/kg, once a day for 4 weeks, from day 1 after the injury) attenuated both thermal and mechanical hyperalgesia, and also attenuated the muscle atrophy. The anti-hyperalgesic activity of PQQ was associated with a significant reduction of pro-inflammatory mediators such as tumor necrosis factor alpha (TNF-α) and lipid peroxide malondialdehyde (MDA) levels. In the present investigation, PQQ is shown to have analgesic effect which was found in the first time, probably through reducing the release of pro-inflammatory mediator and inhibiting oxidative stress.
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Oxaliplatin and paclitaxel are commonly used anti-cancer drugs, but they frequently cause peripheral neuropathic pain. In this study, we investigated the effect of elcatonin, a synthetic eel calcitonin, on oxaliplatin- and paclitaxel-induced neuropathy in rats. The rats were treated with a single dose of oxaliplatin (6 mg/kg, i.p.) or repeated doses of paclitaxel (2 mg/kg, i.p.) on 4 alternate days. ⋯ Pre-administration of elcatonin almost completely prevented cold and mechanical allodynia from being induced by both compounds. These results suggest that elcatonin attenuates oxaliplatin- and paclitaxel-induced neuropathic pain by inhibiting the cellular signaling related to transient receptor potential ankyrin-1 and melastatin-8. Thus, we conclude that administration of elcatonin may improve the quality of life of cancer patients receiving chemotherapy.
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The elusiveness of the mechanism underlying pain is a major impediment in developing effective clinical treatments. We examined whether the phosphorylation of spinal serum- and glucocorticoid-inducible kinase 1 (SGK1) and downstream glutamate receptor interacting protein (GRIP)-associated protein-1 (GRASP-1)/Rab4-dependent GluR1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) recycling play a role in inflammatory pain. After intraplantar injection of complete Freund's adjuvant (CFA), we assessed thermal hyperalgesia using the Hargreaves test and analyzed dorsal horn samples (L4-5) using Western blotting, coprecipitation, and immunofluorescence. ⋯ Intrathecal 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, an AMPAR antagonist, 1, 3, and 10 μM, 10 μL/rat) attenuated the hyperalgesia and GluR1 trafficking caused by CFA; however, it had no effect on SGK1 phosphorylation. Small interfering RNA targeting Rab4 hindered the CFA-induced hyperalgesia and the associated GluR1 trafficking and Rab4-GluR1 coprecipitation. Our results suggest that spinal SGK1 phosphorylation, which subsequently triggers the GRASP-1/Rab4 cascade, plays a pivotal role in CFA-induced inflammatory pain by regulating GluR1-containing AMPAR recycling in the dorsal horn.
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GABA-A receptor positive allosteric modulators (PAMs) mediate robust analgesia in animal models of pathological pain, in part via enhancing injury-induced loss of GABA-A-α2 and -α3 receptor function within the spinal cord. As yet, a lack of clinically suitable tool compounds has prevented this concept being tested in humans. Prior to assessing the efficacy of GABA-A receptor PAMs in a human volunteer pain model we have compared compounds capable of variously modulating GABA-A receptor function in comparable rat models of capsaicin-induced acute nocifensive flinching behaviour and secondary mechanical hypersensitivity. ⋯ This was surprising as both NS11394 and TPA023 robustly attenuated late phase (6-30 min post-injection) capsaicin-induced flinching, a pain-like behaviour that is putatively driven by peripheral and central sensitizing mechanisms. Diazepam also attenuated capsaicin-induced nocifensive behaviours, albeit at doses previously shown to impair locomotor function. Our data indicate that GABA-A receptor PAMs with optimal selectivity and efficacy profiles reduce centrally-mediated mechanical hypersensitivity in capsaicin-injected rats, an observation that we expect can translate directly to human volunteer studies.