Hyperalgesia mechanisms

Memantine also blocks and reverses thermal hyperalgesia, mechanical al-lodynia in rat models of painful mononeuropathy without obvious effects on motor reflexes following systemic (Carlton and Hargett 1995 Eisenberg et al. 1993,1995 Suzuki et al. 2001) and local spinal administration (Chaplan et al. 

Davis A, Perkins M The involvement of bradykinin B1 and B2 receptor mechanisms in cytokine-induced mechanical hyperalgesia in the rat. Br J Pharmacol 1994 113 63-68. 

Baghdoyan, H. A. (2006). Hyperalgesia induced by REM sleep loss a phenomenon in search of a mechanism. Sleep 29, 137-9. 

Clinical pain is characterized by the presence of spontaneous pain or hypersensitivity to pain-provoking stimuli. Hypersensitivity includes pain produced by low-intensity stimuli that normally only elicit an innocuous sensation (allodynia), or an exaggerated response to a noxious stimulus (hyperalgesia). There are two distinct forms of clinical pain, the pain that occurs after tissue injury or inflammatory diseases (inflammatory pain) and the pain associated with a lesion or disease of the nervous system (neuropathic pain). Although the mechanisms responsible for the initiation and maintenance of these pains differ, they are both characterized by heightened... 

Despite intensive research on the neurobiological mechanisms of chronic pain, this therapeutic area remains one of the least satisfactorily covered by current drugs. There is considerable preclinical evidence that hyperalgesia and allody-nia following peripheral tissue or nerve injury is not only due to an increase in the sensitivity of primary afferent nociceptors at the site of injury but also depends on NMDA receptor-mediated central changes in synaptic excitabihty (Zieglgansberger and Tolle 1993 Sandkiihler and Liu 1998 Hide 2000 Parsons 2001 Fundytus 2001). 

The uncompetitive NMDA receptor antagonist ketamine has been available for clinical use as an anaesthetic for 40 years (Domino et al. 1965). Ketamine is effective in various animal models of hyperalgesia and allodynia and has been reported to have antinociceptive effects in some of these models at doses devoid of obvious side-effects. Others, however, have reported that the effects of ketamine are only seen at doses producing ataxia (see Parsons 2001 for review). Ketamine reportedly inhibits the area of secondary hyperalgesia induced by chemical (Park et al. 1995) or thermal stimuli (Ilkjaer et al. 1996 Warncke et al. 1997) and inhibits temporal siunmation of repeated mechanical (Warncke et al. 1997) and electrical stimuli (Arendtnielsen et al. 1995 Andersen et al. 

Chu LF, Angst MS, Clark D Opioid-induced hyperalgesia in humans Molecular mechanisms and clinical considerations. 

Chronic constriction injury (CCI) models (Bennett and Xie, 1988 Kim and Chung, 1992 Mosconi and Kruger, 1996) have been used to examine chronic pain states in experimental animals. In these models, intrathecally administered a2-agonists reduced mechanical allodynia and thermal hyperalgesia that developed following nerve constriction (Levy et al., 1994 Yaksh et al., 1995). This... 

Zahn, P. K. and Brennan, T. J. Intrathecal metabotropic glutamate receptor antagonists do not decrease mechanical hyperalgesia in a rat model of postoperative pain, Anesth. Analg. 1998, 87, 1354-1359. 

L-701,324 has been shown to reverse the inflammation-induced mechanical hyperalgesia in rats without affecting the accompanying carrageenan-induced paw edema (Laird et al., 1996). 

Both remacemide and its des-glycinyl-metabolite inhibit the inflammatory, mechanical hyperalgesia as well as the edema induced by injection of carrageenan or complete Freunds adjuvant into the rat hind paw (Asghar et al.,... 

Laird, J. M. A., Mason, G. S., Webb, J., Hill, R. G., Hargreaves, R. J. Effects of a partial agonist and a full antagonist acting at the glycine site of the NMDA receptor on inflammation-induced mechanical hyperalgesia in rats, Br. J. Pharmacol. 1996, 117, 1487-1492. 

Sutton, J.L., Maccecchini, M.L., Kajander, K.C. The kainate receptor antagonist 2S,4R-4-methylglutamate attenuates mechanical allodynia and thermal hyperalgesia in a rat model of nerve injury, Neuroscience 1999, 91, 283-292. 

Further experimental evidence for the involvement of SP in pain perception came from knock-out animals. Mice, in which the preprotachykinin A gene was disrupted, showed significantly reduced responses in tests that involved more intense noxious stimuli (Cao et al., 1998). De Felipe et al. (1998) disrupted the N receptor, and found the characteristic amplification ( wind up ) and intensity coding of nociceptive reflexes to be absent. NK receptor knockout mice show no changes in acute nociception tests. In contrast, SP and NKi receptor knock-out mice show reduction in responses to inflammatory stimuli. Nerve injury-induced mechanical but not thermal hyperalgesia is attenuated in NKi receptor knock-out mice, when inducing chronic neuropathic pain by unilateral ligation of the L5 spinal nerve (Mansikka et al., 2000). 

Studies to elucidate the functional role of NO have used inhibitors of NO synthase such as L-NAME and L-NMMA (see below). Systemic and intrathecal injections of NO synthase inhibitors have been shown to reduce noxious responses to formalin and carrageenan-induced hyperalgesia (Sakurada et al., 2001). Furthermore, NO-induced mechanical hyperalgesia has been reported to be mediated by supraspinal centers and does not occur in in vitro preparations of the spinal cord. 

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