Articles: hyperalgesia.
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Preclinical evidence suggests that opioid withdrawal induces central sensitization (CS) that is maintained by supraspinal contributions from the descending pain modulatory system (DPMS). Here, in healthy human subjects we use functional magnetic resonance imaging to study the supraspinal activity during the withdrawal period of the opioid remifentanil. We used a crossover design and thermal stimuli on uninjured skin to demonstrate opioid withdrawal-induced hyperalgesia (OIH) without a CS-inducing peripheral stimulus. ⋯ Only in these subjects did opioid infusion and withdrawal induce a rise in activity in the mesencephalic-pontine reticular formation (MPRF), an area of the DPMS that has been previously shown to be involved in states of CS in humans, which became significant during the withdrawal phase compared with nonresponders. Paradoxically, this opioid withdrawal-induced rise in MPRF activity shows a significant negative correlation with the behavioral OIH score indicating a predominant inhibitory role of the MPRF in the responders. These data illustrate that in susceptible individuals central mechanisms appear to regulate the expression of OIH in humans in the absence of tissue injury, which might have relevance for functional pain syndromes where a peripheral origin for the pain is difficult to identify.
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Syntaxin 1A is a membrane protein playing an integral role in exocytosis and membrane trafficking. The superficial dorsal horn (SDH) of the spinal cord, where nociceptive synaptic transmission is modulated, is rich in this protein. We recently reported that peripheral nerve ligation-induced nociceptive responses are considerably enhanced in syntaxin 1A-knockout mice [Takasusuki T, Fujiwara T, Yamaguchi S, Fukushima T, Akagawa K, Hori Y (2007) Eur J Neurosci 26:2179-2187]. ⋯ These results indicate a possible involvement of syntaxin 1A downregulation in the late maintenance phase of peripheral nerve injury-induced allodynia. In addition, syntaxin 1A knockdown by ribonucleic acid interference enhanced the axonal elongation and sprouting of spinal dorsal horn neurons in culture, suggesting that PSNL-induced syntaxin 1A downregulation may result in the rearrangement of the synaptic connections between neurons in the spinal dorsal horn. Taken together, it is possible to conclude that syntaxin 1A might be involved in spinal nociceptive plasticity induced by peripheral nerve injury.
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Phosphinositide 3-kinase (PI3K), Akt, and their downstream kinase, mammalian target of rapamycin (mTOR), are implicated in neural plasticity. The functional linkages of this signaling cascade in spinal dorsal horn and their role in inflammatory hyperalgesia have not been elucidated. ⋯ Intrathecal injection of Substance P activated this cascade (increased phosphorylation) and resulted in hyperalgesia, both of which effects were blocked by intrathecal wortmannin and rapamycin. Together, these findings reveal that afferent inputs trigged by peripheral inflammation initiate spinal activation of PI3K-Akt-mTOR signaling pathway, a component of which participates in neuronal circuits of facilitated pain processing.
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It was previously reported that in 5 patients with small-fiber neuropathy, neuropathic pain, and hyperalgesia, application of a single, brief electrical stimulus to the skin could give rise to 2 afferent impulses in a C-nociceptor fiber. These double spikes, which are attributed to unidirectional conduction failure at branch points in the terminal arborisation, provide a possible mechanism for hyperalgesia. We here report that similar multiple spikes are regularly observed in 3 rat models of neuropathic pain: nerve crush, nerve suture, and chronic constriction injury. ⋯ Whereas only double spikes had previously been described in patients, in these more extensive recordings from rats we found that triple spikes could also be observed after a single electrical stimulus. The results strengthen the suggestion that multiple spiking, because of impaired conduction in the terminal branches of nociceptors, may contribute to hyperalgesia in patients with neuropathic pain. Double and triple spikes in c-nociceptors, caused by impaired conduction in terminal branches, may be an important cause of hyperalgesia in patients with neuropathic pain.
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Herpes zoster characterized by clustered vesicles and severe pain is caused by reactivation of varicella-zoster virus in the sensory ganglion in humans. In some herpes zoster patients, pain persists long after healing of the skin lesions, which is postherpetic neuralgia. Patients with postherpetic neuralgia report various types of pain. ⋯ The mechanisms that underlie the induction and maintenance of herpetic pain and postherpetic neuralgia remain unclear. Therefore we attempted to establish animal models of herpetic pain and postherpetic neuralgia. This review summarizes our findings regarding the development of mouse models of herpetic pain and postherpetic neuralgia, pharmacological characterization of mouse models, mechanisms of allodynia and risk factors for postherpetic neuralgia.