Nociception hyperalgesia

Nociceptive neurons in the spinal cord as well as in higher centres such as the thalamus and cortex can also undergo alterations in activity following chronic peripheral changes and trauma (Table 1). These changes are typically long-term in nature and lead to the clinical syndromes of centrally maintained pain (secondary hyperalgesia, allodynia, spontaneous pain). Alterations... 

Garcia-Martinez, C., Humet, M., Pla-nells-Cases, R., Gomis, A., Caprini, M., ViANA, F., Pena, E. D., Sanchez-Baeza, F., Carbonell, T, Felipe, C D., Perez-Paya, E., Belmonte, C., Messeguer, A., and Ferre-Montiel, A. Attenuation of thermal nociception and hyperalgesia by VRl blockers. Proc. Natl. Acad. Sci. USA 2002, 99, 2374-2379. 

Bradykinin b2 Human cDNA Asthma, arthritis, cancer, hypertension, inflammation, migraine, myocardial ischemia, pain, rhinitis, diabetes, cystic fibrosis, nociception Vasodilatation, stimulation of natriuresis-diuresis in kidney, smooth muscle contraction, induction of hyperalgesia, edema, neuroprotection... 

Evidence from experimental pain research has revealed that mGluRs play a pivotal role in nociceptive processing, inflammatory pain and hyperalgesia. mGluRs have been implicated in dorsal horn neuronal nociceptive responses and pain associated with short-term inflammation (Neugebauer 2002) as well as its emotional component involving hmbic structures such as the amygdala (Han et al. 2004). 

In contrast to the analgesic role of leu- and met-enkephalin, an analgesic action of dynorphin A—through its binding to (kappa) opioid receptors—remains controversial. Dynorphin A is also found in the dorsal horn of the spinal cord, where it may play a critical role in the sensitization of nociceptive neurotransmission. Increased levels of dynorphin can be found in the dorsal horn after tissue injury and inflammation. This elevated dynorphin level is proposed to increase pain and induce a state of long-lasting hyperalgesia. The pronociceptive action of dynorphin in the spinal cord appears to be independent of the opioid receptor system but dependent on the activation of the bradykinin receptor. Moreover, dynorphin A can bind and activate the N -methyl-D-aspartate (NMDA) receptor complex, a site of action that is the focus of intense therapeutic development. 

Taken together there is some direct proof for a functional contribution of spinal NMDA receptors in the process of induction of hyperalgesia by conditional spinal NR1 knockout animals or spinal NR1 knock-down experiments. While at least indirect evidence suggests a correlation between upregulation of the NMDA receptor activity and nociception, the interpretation of the impact of knocking out NR2 subunits needs further detailed research. 

Derivatization of kynurenic acid leads to far more potent and selective antagonists such as 7-chloro-kynurenic acid or 5,7-dichlorokynurenic acid (Kemp et al., 1988 Baron et al., 1990) which have been shown to inhibit glycine-induced tailflick facilitation (i.e attenuation of glycine-induced hyperalgesia) or the late phase of formalin-induced nociception when given intrathecally (Kolhekar et al., 1994, Chapman et al., 1995). Nevertheless kynurenic acid derivatives are still hampered by a poor blood - brain barrier penetration and hence a low CNS availability. 

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). 

Animal models of nociception can be divided according to the therapeutic indication Acute Pain, Migraine Pain, Inflammatory Pain, Visceral Pain, Neuropathic Pain. Different degrees of chronification (up to weeks in neuropathic pain models) and different stimuli (mechanical, thermal, chemical, electrical) are used depending on the experimental question. In most cases a nociceptive threshold (e g. withdrawal latency of a paw) is determined. Sometimes, nociceptive intensities are determined e.g. in order to quantify hyperalgesia. 

We expected that (-)-TAN-67 will be used for the detailed investigation of both the existence and the pharmacological effects of a <5i opioid receptor, and that the (+)-TAN-67-induced nociception may be a unique pharmacological model for the elucidation of pain mechanisms. Moreover, the hyperalgesia produced by (+)-TAN-67 could be one of the neuropathic pain models. We hope that the (+)-TAN-67-induced nociception will be used for the development of analgesics for neuropathic pain, for which morphine indicates little or no effect. 

Activation of nociceptor PKRs by Bv8 in rats and mice produces nociceptive sensitization to thermal and mechanical stimuli, without inducing any spontaneous, overt nocifensive behavior, or local inflammation. Very low doses of Bv8 (50 fmol) injected into the paw induce a decrease in the nociceptive threshold that reaches the maximum in 1 h and disappears in 2-3 h. The same dose i.th., or higher doses by systemic routes (s.c. and i.v.), induces hyperalgesia with a characteristic biphasic time-course the first peak occurs in 1 h and the second peak invariably in 4—5 h. The first phase depends on a direct action on nociceptors, because it resembles that... 

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