Pain
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Olesoxime is a small cholesterol-like molecule that was discovered in a screening program aimed at finding treatment for amyotrophic lateral sclerosis and other diseases where motor neurons degenerate. In addition to its neuroprotective and pro-regenerative effects on motor neurons in vitro and in vivo, it has been shown to have analgesic effects in rat models of painful peripheral neuropathy due to vincristine and diabetes. We used a rat model of painful peripheral neuropathy produced by the chemotherapeutic agent, paclitaxel, to determine whether olesoxime could reverse established neuropathic pain. ⋯ Giving olesoxime during the exposure to paclitaxel significantly and permanently reduced the severity of mechano-allodynia and mechano-hyperalgesia and significantly reduced the amount of sensory terminal arbor degeneration. Olesoxime targets mitochondrial proteins and its effects are consistent with the mitotoxicity hypothesis for paclitaxel-evoked painful peripheral neuropathy. We conclude that olesoxime may be useful clinically for both the prevention and treatment of paclitaxel-evoked painful peripheral neuropathy.
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Cold allodynia is a common sign of neuropathic pain patients but its underlying mechanisms are still largely unknown, partly because the populations of neurons responding to cold stimuli and their transduction mechanisms have not been fully determined. We report a patient with a small-fiber neuropathy of unknown origin, whose main complaint is cold allodynia. ⋯ These findings provide the first direct evidence in human of abnormal peripheral nociceptor behavior potentially responsible for cold allodynia. The responsiveness of C-nociceptors to menthol suggests an abnormal expression or function of TRPM8 channels in this patient with a small-fiber polyneuropathy.
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In adult patients with migraine, transcranial magnetic stimulation (TMS) has been used to examine cortical excitability between attacks, but there have been discrepant results. No TMS study has examined cortical excitability in children or adolescents with migraine. Here, we employed TMS to study regional excitability of the occipital (phosphene threshold [PT] and suppression of visual perception) and motor (resting motor threshold and cortical silent period) cortex in ten children suffering from migraine without aura and ten healthy age-matched controls. ⋯ Motor cortex excitability was not altered in patients and did not change during the migraine cycle. These findings show that pediatric migraine without aura is associated with a systematic shift in occipital excitability preceding the migraine attack. Similar systematic fluctuations in cortical excitability might be present in adult migraineurs and may reflect either a protective mechanism or an abnormal decrease in cortical excitability that predisposes an individual to a migraine attack.
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Endometriosis is a painful disorder defined by extrauteral endometrial growths whose contribution to pain symptoms is poorly understood. Endometriosis is created in rats by autotransplanting on abdominal arteries pieces of either uterus (ENDO), which form cysts, or fat (shamENDO), which do not form cysts. ENDO, but not shamENDO induces vaginal hyperalgesia. ⋯ The increases in ENDO-induced hyperalgesia produced by the sham-cyst-removal surgery were smaller in proestrus than in other estrous stages. During the other stages (but not during proestrus), sympathetic innervation of the cysts increased. These results suggest that maintenance of ENDO-induced vaginal hyperalgesia requires continued presence of at least some ectopic endometrial tissue, and that surgical treatment that fails to remove ectopic endometrial tissue can exacerbate the hyperalgesia, possibly due in part to an increase in the cysts' sympathetic innervation.
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The central processing of peripheral nociceptive messages is highly controlled by the activity of local inhibitory networks in the spinal cord and supraspinal centers. Recently, it has been shown that endogenous 3alpha-reduced neurosteroids (3alphaNS) exert a significant spinal antinociception by potentiating GABA(A) receptor function. Because endogenous 3alphaNS can be produced in many relay structures of the nociceptive system, we tested the potential analgesic efficacy of promoting the production of neurosteroids by using etifoxine (ETX, 50mg/kg i.p.). ⋯ Both the curative and preventive effects of ETX on pain symptoms were mediated by the production of 3alphaNS as demonstrated in animals treated with the enzymatic inhibitor provera (6-medroxyprogesterone acetate; 20mg/kg s.c.). Altogether, this study shows for the first time that promoting 3alphaNS could be a possible therapeutic strategy to treat neuropathic pain symptoms. Since ETX is already available as an anxiolytic, its use in humans, provided that its analgesic properties are confirmed, could be rapidly considered.