Opioid receptors knockout

Zhu Y, King MA, Schuller AGP, Nitsche JF, Reidl M, Elde RP, Unterwald E, Pasternak GW, Pintar JE. Retention of supraspinal delta-like analgesia and loss of morphine tolerance in opioid receptor knockout mice. Neuron 1999 24 243-252. 

The pharmacology of delta ligands was investigated in opioid receptor knockout mice, and data from these compounds have been more difficult to... 

In conclusion, the in vivo activity of available delta opioids is complex. DPDPE, or even Delt, administered ICV seems to recruit mu receptors and, from all the data, it appears that delta agonists often have mixed mu/ delta activities. More selective delta agonists need to be produced to explore delta receptor pharmacology. The examination of nonanalgesic activities of delta ligands in opioid receptor knockout mice has been very informative while the convulsive effect of SNC 80 seems indeed delta receptor mediated, the addictive activity of Delt most probably results from mu receptor activation and the immunosuppressive action of NTI is mediated by a nonopioid mechanism. 

Gaveriaux-Ruff C, Filliol D, SimoninF, Matthes HWD, Kieffer BL (2001) Immunosuppression by 8-opioid antagonist naltrindole 5- and triple p/5/K-opioid receptor knockout mice reveal a nonopioid activity. J Pharmacol Exp Ther 298 1193-1198... 

Castane A, Robledo P, Matifas A, Kieffer BL, Maldonado R (2003) Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice. Eur J Neurosci 17 155-159... 

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. 

In line with the latter observations, the rewarding effects of morphine are absent in knockout mice lacking receptors but persist when either of the other opioid receptors are ablated. In the VTA, opioids cause an inhibition of GABAergic inhibitory interneurons, which leads eventually to a disinhibition of dopamine neurons. 

Using superfusion experiments, electrophysiological techniques, pithed animal preparations, and experiments in which transmitter release was determined indirectly via the end-organ response (e.g., twitch response of vas deferens preparations), numerous presynaptic opioid receptors have been identified (Table 2). For the identification of the receptors, classical drug tools were used for future studies, knockout mice (now available for each of the four opioid receptor subtypes) and special nucleotides (e.g., antisense oligodeoxynucleotides or short interfering... 

Capogna M, Gahwiler BH, Thompson SM (1993) Mechanism of mu-opioid receptor-mediated presynaptic inhibition in the rat hippocampus in vitro. J Physiol 470 539-58 Chemelli RM, Willie JT, Sinton CM et al (1999) Narcolepsy in orexin knockout mice molecular genetics of sleep regulation. Cell 98 437-51... 

The activity of a prototypical delta antagonist was also tested in vivo. The immunosuppressive effect of NTI was maintained in delta receptor knockout mice, as well as in mice lacking all three opioid receptors [68], opening the search for a novel molecular target for this widely used delta opioid compound. 

The delta opioid knockout mice demonstrated behaviors consistent with anxiogenic- and depressivelike responses, suggesting that delta opioid receptors and endogenous tone of the delta opioid system may play a role in mood states and depression. 

The availability of receptor knockout animals has also helped to illustrate cannabinoid-opioid interactions. CBi receptor knockout mice had greatly reduced morphine self-administration behavior and less severe naloxone-induced withdrawal signs than wild type animals, although the antinociceptive actions of morphine were unaffected in the knockout animals (40). The rimona-bant-precipitated withdrawal syndrome in THC-treated mice was significantly attenuated in animals with knockout of the pro-enkephalin gene (48). Knockout of the p opioid (OP3) receptor also reduced rimonabant-induced withdrawal signs in THC-treated mice, and there was an attenuated naloxone withdrawal syndrome in morphine-dependent CBi knockout mice (49,50). 

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