Pain
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Pro-inflammatory cytokine high mobility group box-1 (HMGB-1) is involved in inflammation in the central nervous system, but less is known about its biological effects in the peripheral nervous system. In the present study, the role of HMGB-1 in the primary afferent nerve was investigated in the context of the pathophysiology of peripheral nerve injury-induced pain hypersensitivity. Real-time PCR confirmed an increase in HMGB-1 mRNA expression in the dorsal root ganglion (DRG) and spinal nerve at 1 day after spinal nerve ligation (SNL). ⋯ Receptor for advanced glycation end products (RAGE), one of the major receptors for HMGB-1, was expressed in the primary afferent neurons and SGCs in the DRG, as well as in Schwann cells in the spinal nerve. These results indicate that HMGB-1 is synthesized and secreted into the DRG and spinal nerve, and contributes to the development of neuropathic pain after nerve injury. Blocking HMGB-1/RAGE signalling might thus be a promising therapeutic strategy for the management of neuropathic pain.
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The involvement of the 5-HT(7) receptor in nociception and pain, particularly chronic pain (i.e., neuropathic pain), has been poorly investigated. In the present study, we examined whether the 5-HT(7) receptor participates in some modulatory control of nerve injury-evoked mechanical hypersensitivity and thermal (heat) hyperalgesia in mice. Activation of 5-HT(7) receptors by systemic administration of the selective 5-HT(7) receptor agonist AS-19 (1 and 10mg/kg) exerted a clear-cut reduction of mechanical and thermal hypersensitivities that were reversed by co-administering the selective 5-HT(7) receptor antagonist SB-258719. ⋯ The 5-HT(7) receptor co-localized with GABAergic cells in the dorsal horn of the spinal cord, suggesting that the activation of spinal inhibitory GABAergic interneurons could contribute to the analgesic effects of 5-HT(7) receptor agonists. In addition, a significant increase of 5-HT(7) receptors was found by immunohistochemistry in the ipsilateral dorsal horn of the spinal cord after nerve injury, suggesting a "pain"-triggered regulation of receptor expression. These results support the idea that the 5-HT(7) receptor subtype is involved in the control of pain and point to a new potential use of 5-HT(7) receptor agonists for the treatment of neuropathic pain.
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Temporal variations in cancer pain intensity are highly prevalent, and are often difficult to manage. However, the phenomenon is not well understood: several definitions and approaches to classification and bedside assessment of cancer breakthrough pain (BTP) have been described. The present study is a systematic review of published literature on cancer BTP to answer the following questions: which terms and definitions have been used; are there validated assessment tools; which domains of BTP do the tools delineate, and which items do they contain; how have assessment tools been applied within clinical studies; and are there validated classification systems for BTP. ⋯ Analysis of these publications indicates a range of overlapping but distinct definitions have been used to characterize BTP; 42 of the included papers presented one or more ways of classifying BTP; and while 10 tools to assess patients' experience of BTP were identified, only 2 have been partially validated. We conclude that there is no widely accepted definition, classification system or well-validated assessment tool for cancer-related breakthrough pain, but there is strong concurrence on most of its key attributes. With further work in this area, an internationally agreed upon definition and classification system for cancer-related breakthrough pain, and a standard approach on how to measure it, hold the promise to improve patient care and support research in this poor-prognosis cancer pain syndrome.
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Randomized Controlled Trial
Increased basal mechanical pain sensitivity but decreased perceptual wind-up in a human model of relative hypocortisolism.
Clinical data have accumulated showing that relative hypocortisolism, which may be regarded as a neuroendocrinological correlate of chronic stress, may be a characteristic of some functional pain syndromes. However, it has not been clarified yet whether deregulations of the hypothalamus-pituitary-adrenal (HPA) axis may directly alter pain perception and thus be causally involved in the pathophysiology of these disorders. To test this hypothesis, we performed a randomized placebo-controlled crossover trial in N=20 healthy drug-free volunteers (median age 24yrs) and analyzed the effects of metyrapone-induced hypocortisolism on quantitatively assessed basal mechanical pain sensitivity (1.5-13m/s impact stimuli), perceptual wind-up (9m/s impact stimuli at 1Hz) and temporal summation of pain elicited by inter-digital web pinching (IWP; 10N pressure stimuli for 2min). ⋯ Perceptual wind-up by contrast was reduced when cortisol synthesis was blocked (p<.05). This result is reminiscent of findings from animal studies showing a reversal of NMDA receptor activation by glucocorticoid receptor antagonists in neuropathic pain models. Our results speak in favor of a potential causal role of HPA axis alterations in pain chronicity.