Articles: hyperalgesia.
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The activation of spinal cord glial cells has been implicated in the development of neuropathic pain upon peripheral nerve injury. The molecular mechanisms underlying glial cell activation, however, have not been clearly elucidated. In this study, we found that damaged sensory neurons induce the expression of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and inducible nitric-oxide synthase genes in spinal cord glial cells, which is implicated in the development of neuropathic pain. ⋯ The nerve injury-induced spinal cord microglia and astrocyte activation is reduced in the toll-like receptor 2 knock-out mice. Similarly, the nerve injury-induced pro-inflammatory gene expression in the spinal cord is also reduced in the toll-like receptor 2 knock-out mice. These data demonstrate that toll-like receptor 2 contributes to the nerve injury-induced spinal cord glial cell activation and subsequent pain hypersensitivity.
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The biophysical properties of a tetrodotoxin resistant (TTXr) sodium channel, Na(V)1.8, and its restricted expression to the peripheral sensory neurons suggest that blocking this channel might have therapeutic potential in various pain states and may offer improved tolerability compared with existing sodium channel blockers. However, the role of Na(V)1.8 in nociception cannot be tested using a traditional pharmacological approach with small molecules because currently available sodium channel blockers do not distinguish between sodium channel subtypes. We sought to determine whether small interfering RNAs (siRNAs) might be capable of achieving the desired selectivity. ⋯ One of the siRNA probes showing a robust knockdown of Na(V)1.8 current was evaluated for in vivo efficacy in reversing an established tactile allodynia in the rat chronic constriction nerve-injury (CCI) model. The siRNA, which was delivered to lumbar dorsal root ganglia (DRG) via an indwelling epidural cannula, caused a significant reduction of Na(V)1.8 mRNA expression in lumbar 4 and 5 (L4-L5) DRG neurons and consequently reversed mechanical allodynia in CCI rats. We conclude that silencing of Na(V)1.8 channel using a siRNA approach is capable of producing pain relief in the CCI model and further support a role for Na(V)1.8 in pathological sensory dysfunction.
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Anesthesia and analgesia · May 2007
Comparative StudyPerineural resiniferatoxin prevents the development of hyperalgesia produced by loose ligation of the sciatic nerve in rats.
The vanilloid receptors (TRPV1) are found in peripheral nerve fibers; their stimulation by capsaicin leads to release of calcitonin gene-related peptide and other neuropeptides participating in neuroinflammation. On the other hand, various inflammatory mediators, released after nerve damage, can activate or sensitize the TRPV1 receptors. These findings together suggest a protective effect of TRPV1 receptor blockade in neuropathy. In the present study, we tested the hypothesis that perineural resiniferatoxin (RTX) can prevent the development of hyperalgesia caused by placing loosely constrictive ligatures around the sciatic nerve. ⋯ Perineural RTX prevents the development of neuropathy caused by placing loosely constrictive ligatures on the sciatic nerve. Perioperative use of drugs acting via the TRPV1 receptors may hold the promise for preventing neuropathic pain after surgery on peripheral nerves.
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The aim of this study was to differentiate the processing of nociceptive information, matched for pain intensity, from capsaicin-induced hyperalgesic vs. control skin at multiple levels in the trigeminal nociceptive pathway. Using an event-related fMRI approach, 12 male subjects underwent three functional scans beginning 1 h after topical application of capsaicin to a defined location on the maxillary skin, when pain from capsaicin application had completely subsided. Brush and two levels of painful heat (low-Thermal-1 and high-Thermal-2) were applied to the site of capsaicin application and to the mirror image region on the opposite side. ⋯ Thus, trigeminal nociceptive regions showed increased activation in the context of perceptually equal pain levels. Beyond these regions, contrast analyses of capsaicin vs. control skin stimulation indicated significant changes in bilateral dorsolateral prefrontal cortex and amygdala. The involvement of these emotion-related regions suggests that they may be highly sensitive to context, such as prior experience (application of capsaicin) and the specific pain mechanism (hyperalgesic vs. normal skin).
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Comparative Study
Spinal NK-1 receptor expressing neurons mediate opioid-induced hyperalgesia and antinociceptive tolerance via activation of descending pathways.
Opioids can induce hyperalgesia in humans and in animals. Mechanisms of opiate-induced hyperalgesia and possibly of spinal antinociceptive tolerance may be linked to pronociceptive adaptations occurring at multiple levels of the nervous system including activation of descending facilitatory influences from the brainstem, spinal neuroplasticity, and changes in primary afferent fibers. Here, the role of NK-1 receptor expressing cells in the spinal dorsal horn in morphine-induced hyperalgesia and spinal antinociceptive tolerance was assessed by ablating these cells with intrathecal injection of SP-saporin (SP-SAP). ⋯ Thus, NK-1 receptor expressing neurons play a critical role in sustained morphine-induced neuroplastic changes which underlie spinal excitability reflected as thermal and tactile hypersensitivity to peripheral stimuli, and to reduced antinociceptive actions of spinal morphine (i.e., antinociceptive tolerance). Ablation of these cells likely eliminates the ascending limb of a spinal-bulbospinal loop that engages descending facilitation and elicits subsequent spinal neuroplasticity. The data may provide a basis for understanding mechanisms of prolonged pain which can occur in the absence of tissue injury.