Mechanisms antinociception

The three prototype mixed p agonist/S antagonists described in this chapter have excellent potential as analgesics with low propensity to produce tolerance and dependence. The pseudotetrapeptide DIPP-NH2[ ] has already been shown to produce a potent analgesic effect, less tolerance than morphine, and no physical dependence upon chronic administration. In preliminary experiments, the tetrapeptides DIPP-NH2 and DIPP-NH2[T] were shown to cross the BBB to some extent, but further structural modifications need to be performed in order to improve the BBB penetration of these compounds. The Tyr-Tic dipeptide derivatives can also be expected to penetrate into the central nervous system because they are relatively small, lipophilic molecules. In this context, it is of interest to point out that the structurally related dipeptide H-Dmt-D-Ala-NH-(CH2)3-Ph (SC-39566), a plain p-opioid agonist, produced antinociception in the rat by subcutaneous and oral administration [72], As indicated by the results of the NMR and molecular mechanics studies, the conformation of the cyclic p-casomorphin analogue H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] is stabilized by intramolecular hydrogen bonds. There-... 

Goncales CEP, Araldi D, Panatieri R B, Rocha J B T, Zeni G and Nogueira C W (2005), Antinociceptive properties of acetylenic thiophene and furan derivatives Evidence for the mechanism of action , Life Sciences, 76, 2221-2234. 

Histamine also induces antinociceptive (i.e. pain-relieving) responses in animals after microinjection into several brain regions [73, 74]. H, and H2 mechanisms are significant and both neuronal and humoral mechanisms may be involved. Brain H2 receptors appear to mediate some forms of endogenous analgesic responses, especially those elicited by exposure to stressors [75]. Many of the modulatory actions of histamine discussed above appear to be activated as part of stress responses. For reasons that remain unclear, histamine releasers, such as thioperamide, show only mild, biphasic antinociceptive actions, even though histamine is a potent and effective analgesic substance. Outside the brain, both H and H3 receptors exist on certain types of sensory nerves and activation of these receptors promotes and inhibits, respectively, peripheral nerve transmission related to pain and/or inflammation [76,77]. 

Kim HS, Oh KW, Rheu HM, Kim SH. (1992). Antagonism of U-50,488H-induced antinociception by ginseng total saponins is dependent on serotonergic mechanisms. Pharmacol Biochem Behav. 42(4) 587-93. 

Kiritsy-Roy JA, Shyu BC, Danneman PJ, Morrow TJ, Beiczynski C, Casey KL. (1994). Spinai antinociception mediated by a cocaine-sensitive dopaminergic supraspinai mechanism. Brain Res. 644(1) 109-16. 

Lichtman AH, Martin BR. (1991). Cannabinoid-induced antinociception is mediated by a spinal alpha 2-noradrenergic mechanism. Brain Res. 559(2) 309-14. 

Zarrindast MR, Nami AB, Farzin D. (1996). Nicotine potentiates morphine antinociception a possible cholinergic mechanism. Eur Neuropsychopharmacoi. 6(2) 127-33. 

Zarrindast MR, Pazouki M, Nassiri-Rad S. (1997). Involvement of cholinergic and opioid receptor mechanisms in nicotine-induced antinociception. Pharmacoi Toxicoi. 81(5) 209-13. 

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. 

Vanderah TW et al Mechanisms of opioid-induced pain and antinociceptive tolerance Descending facilitation and spinal dynorphin. Pain 2001 92 5. [PMID 11323121]... 

Idanpaan, J. J., Kalso, E. A., Seppala, T.. Antinociceptive actions of dexmedetomidine and the K-opioid agonist U-50488H against noxious thermal, mechanical and inflammatory stimuli, J. Pharmacol. Exp. Ther. 1994, 271, 1306-1313. 

Miranda, H. F., Pelissier, T., Pinardi, G. Involvement of adrenergic, serotonergic, and opioid mechanisms in tramadol-induced antinociception in mice, Analgesia 1999, 4, 1-7. 

Second, the mechanisms by which altered K+ channels contribute to the development of chronic pain states and what needs must be met by the channels in order to constitute attractive drug targets with respect to the problem of ensuring a specific antinociceptive action will be discussed. Corresponding examples for this will be given. 

Welch, S. P. and Dunlow, L. D. Antinociceptive activity of intrathecally administered potassium channel openers and opioid agonists a common mechanism of action , The Journal of Pharmacology and Experimental Therapeutics 1993, 267, 390-399. 

Coderre, T. J. and Van Empel, I. The utility of excitatory amino acid (EAA) antagonists as analgesic agents. Comparison of the antinociceptive activity of various classes of EAA antagonists in mechanical, thermal and chemical nociceptive tests, Pain 1994, 59, 345-352. 

Epibatidine was shown to be a very potent and selective agonistic ligand of nicotinic acetylcholine receptors. This natural product is effective in various animal models of pain through a pronounced nAChR agonistic mechanism (Ki <100 pm) which is accompanied by severe and nACh-related side-effects (Corey et al. 1993 Rupniak et al., 1994 Boyce et al., 2000). A clear differentiation between antinociceptive activity in animal models of pain and toxic side-effects cannot be determined. Nevertheless there is some activity directed towards the development of epibatidine as an analgesic (Bai et al., 1997). 

Kawamura, M., Kuraishi, Y., Minami, M., Satoh, M. Antinociceptive effect of intrathecally administered antiserum against calcitonin gene-related peptide on thermal and mechanical noxious stimuli in experimental hyperalgesic rats, Brain Res. 1989, 497, 199-203. 

Cheng JK, Chiou LC (2006) Mechanisms of the antinociceptive action of gabapentin. J Pharmacol Sci 100 471-86... 

Abrahamsson C (2000) Neuropeptide Y1- and Y2-receptor-mediated cardiovascular effects in the anaesthetized guinea pig, rat, and rabbit. J Cardiovasc Pharmacol 36 451-8 Ackley MA, Hurley RW, Virnich DE et al (2001) A cellular mechanism for the antinociceptive effect of a kappa opioid receptor agonist. Pain 91 377-88 Aimone LD, Yaksh TL (1989) Opioid modulation of capsaicin-evoked release of substance P from rat spinal cord in vivo. Peptides 10 1127-31... 

Tan-No, K., Taira, A., Inoue, M., Ohshima, K., Sakurada, T., Sakurada, C., Nylander, I., Demuth, H. U., Silberring, J., Terenius, L., Tadano, T., and Kisara, K. (1998). Intrathecal administration of />-hydroxymercuribenzoate or phosphoramidon/bestatin-combined induces antinociceptive effects through different opioid mechanisms. Neuropeptides 32, 411-415. 

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