Mol Pain
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Chronic pain is a major public health problem with limited treatment options. Opioids remain a routine treatment for chronic pain, but extended exposure to opioid therapy can produce opioid tolerance and hyperalgesia. ⋯ Given that mTOR inhibitors are FDA-approved drugs and an mTOR inhibitor is approved for the treatment of several cancers, these findings suggest that mTOR inhibitors will likely have multiple clinical benefits, including anticancer, antinociception/anti-cancer pain, and antitolerance/hyperalgesia. This paper compares the role of mTOR complex 1 in chronic pain, opioid-induced tolerance, and opioid-induced hyperalgesia.
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Neuropeptide Y (NPY) has been implicated in the modulation of pain. Under normal conditions, NPY is found in interneurons in the dorsal horn of the spinal cord and in sympathetic postganglionic neurons but is absent from the cell bodies of sensory neurons. Following peripheral nerve injury NPY is dramatically upregulated in the sensory ganglia. How NPY expression is altered in the peripheral nervous system, distal to a site of nerve lesion, remains unknown. To address this question, NPY expression was investigated using immunohistochemistry at the level of the trigeminal ganglion, the mental nerve and in the skin of the lower lip in relation to markers of sensory and sympathetic fibers in a rat model of trigeminal neuropathic pain. ⋯ This is the first study to provide a comprehensive description of changes in NPY expression in the periphery after nerve injury. Novel expression of NPY in the skin comes mostly from sprouted sympathetic fibers. This information is fundamental in order to understand where endogenous NPY is expressed, and how it might be acting to modulate pain in the periphery.
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Pain in the head neck area is an early symptom in oral cancer, supporting the hypothesis that cancer cells control the activities of surrounding nociceptors at the site of the tumor. Several reports implicate TRPV1 and TRPA1 in cancer pain, although there is a large gap in knowledge since the mechanisms for tumor-induced activation of these TRP receptors are unknown. Interestingly, TRP-active lipids such as linoleic acid, arachidonic acid, hydroxyoctadecadienoic acid and hydroxyeicosatetraenoic acid are significantly elevated in the saliva of oral cancer patients compared to normal patients, supporting a possible linkage between these lipids and oral cancer pain. We therefore hypothesize that oral squamous cell carcinomas release certain lipids that activate TRPV1 and/or TRPA1 on sensory neurons, contributing to the development of oral cancer pain. ⋯ These data reveal a novel mechanism for cancer pain and provide strong direction for future studies evaluating the cellular mechanism regulating the TRP-active lipids by OSCC tumors.
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Previous studies have shown that increased excitability of capsaicin-sensitive DRG neurons and thermal hyperalgesia in rats with short-term (2-4 weeks) streptozotocin-induced diabetes is mediated by upregulation of T-type Ca(2+) current. In longer-term diabetes (after the 8th week) thermal hyperalgesia is changed to hypoalgesia that is accompanied by downregulation of T-type current in capsaicin-sensitive small-sized nociceptors. At the same time pain symptoms of diabetic neuropathy other than thermal persist in STZ-diabetic animals and patients during progression of diabetes into later stages suggesting that other types of DRG neurons may be sensitized and contribute to pain. In this study, we examined functional expression of T-type Ca(2+) channels in capsaicin-insensitive DRG neurons and excitability of these neurons in longer-term diabetic rats and in thermally hypoalgesic diabetic rats. ⋯ Capsaicin-insensitive low-pH-sensitive type of DRG neurons shows diabetes-induced upregulation of Cav3.2 subtype of T-type channels. This upregulation results in the increased excitability of these neurons and may contribute to nonthermal nociception at a later-stage diabetes.
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Pain is the most prominent non-motor symptom observed in patients with Parkinson's disease (PD). However, the mechanisms underlying the generation of pain in PD have not been well studied. We used a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD to analyze the relationship between pain sensory abnormalities and the degeneration of dopaminergic neurons. ⋯ These results suggest that the dopaminergic nigrostriatal pathway may have a role in inhibiting noxious stimuli, and that abnormal inflammatory responses and neural activity in basal ganglia is correlated to pain processing in PD induced by MPTP treatment.