Antinociception antagonist

The existence of further alternative transcripts of MOP was postulated by the observation that in knockout mice with disrupted exon 1, heroin but not morphine was still analgesically active. Based on earlier observations that the antagonist naloxazone blocked morphine-induced antinociception but not morphine-induced respiratory depression, a subdivision of the MOP in pi and p2 was proposed. However, no discrete mRNA for each of these MOP subtypes has been found. It is, however, possible that subtypes of MOPs result from heterodimerization with other opioid receptors or by interaction with other proteins. 

Tables 6.8-6.11 illustrate the wide range of C3 side-chain modified A -THC analogues that have been reported in the literature, together with associated in vitro and in vivo data. The affinity of classical cannabinoid analogues for the CBi receptor has been shown to correlate with depression of spontaneous activity and the production of antinociception, hypothermia and catalepsy in mice, and with psychomimetic activity in humans [93]. However, in some cases, there were unexplained differences between the observed trends in binding affinity and the trends in activity in mouse behavioural models. This may point to differences in efficacy among full agonists, partial agonists and antagonists/inverse agonists, or may reflect differences in in vivo metabolism or blood-brain barrier penetration or a combination of these factors.

Iwamoto, E.T. Locomotor activity and antinociception after putative mu, kappa and sigma opioid receptor agonists in the rat Influence of dopaminergic agonists and antagonists. J Pharmacol Exp Ther 217 451-460, 1981. 

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-... 

Gogas, K. R. and Hough, L. B. Inhibition of naloxone-resistant antinociception by centrally-administered H2 antagonists. /. Pharmacol. Exp. Ther. 248 262-267,1989. 

Biisky EJ, Inturrisi CE, Sad e W, Hruby VJ, Porreca F. (1996). Competitive and non-competitive NMDA antagonists biock the deveiopment of antinociceptive tolerance to morphine, but not to seiective mu or deita opioid agonists in mice. Pain. 68(2-3) 229-37. 

Lichtman AH, Martin BR. (1997). The selective cannabinoid antagonist SR 141716A blocks cannabinoid-induced antinociception in rats. Pharmacol Biochem Behav. 57(1-2) 7-12. 

In 1990, Roussell-UCLAF published a patent disclosing that the tertiary amine (83) is a kappa antagonist [in vitro receptor binding IC50 kappa = 57 nM, mu = 840 nM, dopamine (spiroperidol) = 10,600 nM] which when given to rats at 20 mg/kg s.c. antagonizes the diuresis and antinociception induced by U-50488 (5 mg/kg p.o.) [102]. It remains to be seen whether this... 

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. 

Taniguchi K, Shinjo K, Mizutani M, et al (1997) Antinociceptive activity of CP-101,606, an NMDA receptor NR2B subunit antagonist. Br J Pharmacol 122 809-812 Tempia F, Alojado ME, Strata P, KnOpfel T (2001) Characterization of the mGlnR(l)-mediated electrical and calcium signaling in Purkinje cells of mouse cerebellar slices. J Neurophysiol 86 1389-1397... 

A.B. Malmberg, M.F. Rafferty, T.L. Yaksh, Antinociceptive effect of spinally delivered prostaglandin E receptor antagonists in the formalin test on the rat, Neurosci. Lett. 173 (1994) 193. 

The answer is c. (Hardman, p 527. Katzung, p 516.) Naloxone is a pure opioid antagonist at the (1, K, and 5 receptors. j,-receptor stimulation causes analgesia, euphoria, decreased gastrointestinal (Gl) activity, miosis, and respiratory depression. K-receptor stimulation causes analgesia, dysphoria, and psychotomimetic effects. 5-receptor stimulation is not fully understood in humans, but is associated with analgesia and antinociception for thermal stimuli. 

---