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An Opiate Cocktail that Reduces Morphine Tolerance and Dependence.

Dr.Heckyll

Dr.Heckyll

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Sep 16, 2006
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Doesn't that sound too good to be true?

Curr Biol. 2005 Jun 7;15(11):1028-33.

An Opiate Cocktail that Reduces Morphine Tolerance and Dependence.

He L, Whistler JL.

Ernest Gallo Clinic and Research Center, University of California, San Francisco, 5858 Horton Street, Suite 200, Emeryville, California 94608.

Morphine is an exceptionally effective analgesic whose utility is compromised by the development of tolerance and dependence to the drug. Morphine analgesia and dependence are mediated by its activity at the mu opioid peptide (MOP) receptor []. The MOP receptor is activated not only by morphine, but also by other opiate drugs such as methadone and endogenous opioids such as endorphins. Morphine, however, is a unique opioid agonist ligand because it fails to induce endocytic trafficking of the MOP receptor [], whereas the endogenous ligands and methadone do facilitate endocytosis []. Using the unique pharmacology of the MOP receptor and its proposed existence as an oligomeric structure [], we designed a pharmacological cocktail that facilitates endocytosis of the MOP receptor in response to morphine. This cocktail consists of morphine and a small dose of methadone. Importantly, this cocktail, while retaining full analgesic potency, does not promote morphine dependence. We further demonstrate that dependence is reduced, at least in part, because endocytosis of the MOP receptor in response to morphine prevents the upregulation of N-methyl-D-aspartate (NMDA) receptors.

PMID: 15936273
Click to expand...
 
hussness said:
Can someone explain how/why endocytosis of MOP modulates tolerance and dependence?
Click to expand...

Endocytosis of a receptor promotes short term tolerance to receptor agonists. The classic example are photoreceptors in the retina -- after becoming activated by a photon and transmitting a signal, the receptor is internalized (via endocytosis). After some time, the receptor is 'recycled', and transported once again to the cell surface.

If the receptor wasn't internalized, a brief flash of light would permanently burn into our vision, rather than only lasting for a brief second.

I don't know specifically how this fits into the mu opiate peptide (MOP) receptor, but it's possible that the receptor desensitizes at the cell surface, without any need for endocytosis. If this was the case, activation of the receptor by morphine would leave a 'non-responsive' MOP on the cell surface. In the case of endorphin/methadone activation, the MOP is endocytosed, and then recycled/returned to the cell surface as a new receptor capable of being activated again.
 
this is interesting.

first its antagonists, then DXM, now methadone lol.
 
I've found some pretty interesting stuff on the use of ketamine to get people off opiates. I wonder if the ketamines NMDA & sigma receptor activity is important?
 
Yeah this is definately an interesting thread. I think the genuine research chemical 3-hydroxy PCP is just about the most potent NMDA receptor antagonist known. Interestingly I think it may actually be an opiate antagonist too. So basically what we are saying is these compounds reverse opiate tolerance and dependence. I think this theory has gained quite a bit of acceptance now. I dunno if it works for pcp but ive read peoples accounts that benzos and ketamine both make withdrawing from opiates less harsh.
 
And 3-amino PCP is supposed to be an agonist at the opiatre receptors. What an amazing range of activity can be produced with small modifications to this simple molecule.
 
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