zorn
Bluelighter
There's been a lot of really interesting work recently on blocking the development of opioid tolerance; here's some I happen to have heard about. This doesn't have much practical value; it's here mainly since I thought some Bluelighters might find it interesting (and I'm avoiding work). Hopefully someone will enjoy it.... lemme know if you do.
Beta-arrestin-2
This is the most interesting and least practical approach. The opioid receptors are G protein coupled receptors (GPCRs); when an opioid binds to them, they release part of a special protein called a G protein into the cell, which does various other things that eventually cause the opioid's effects. After the G protein is released, the receptor is marked by an enzyme called G protein receptor kinase (GRK). Sometimes the receptor eventually gets a new G protein and can cause more opioid effects, and sometimes it gets stuck with something called an arrestin, which can disable it or haul it off to the receptor graveyard. Losing receptors this way is believed to be one of the mechanisms underlying the development of opioid tolerance.
The particular arrestin responsible for opioid receptors seems to be beta-arrestin-2. Some researchers recently made a strain of mice lacking the gene for this arrestin, and found that they were supersensitive to opioids -- 1mg/kg morphine corresponded to 5mg/kg in normal mice -- and developed no tolerance at all to opioids. Besides that they appeared perfectly normal. Strangely, the mice did get addicted, and went through withdrawal just like normal mice. The researchers got published in both Science and Nature for their work (the mice got to stay high for a couple weeks, then were killed.) Now if only I could get all my beta-arrestin destroyed....
Incidentally there are two phases of opioid tolerance: acute tolerance, which develops within minutes and fades in hours, and chronic tolerance, which develops and fades over days; the mice experienced neither. The timecourse of acute tolerance sounds suspiciously like that of the rush from i.v. opioids. I'd guess without acute tolerance the rush would wear off only very slowly. Now if only I could get all my beta-arrestin-2 destroyed...
Nature 2000 Dec 7;408(6813):720-3 http://www.nature.com/cgi-taf/DynaPage.taf?file=/natur e/journal/v408/n6813/abs/408720a0_fs.html&dynoptions=doi1005920490
Other stuff
NMDA antagonists (ketamine,DXM,PCP among others) attenuate opioid tolerance, no one seems sure how. Inhibitors of nitric oxide synthase seem to do the same thing. A new research drug involved with substance P system similarly blocks tolerance (see papers below).
Closer to clinical use are studies using opioid antagonists (eg naloxone), which are easily available and tested. One study found that very tiny doses of an antagonist along with an opioid maintained the analgesic ability (presumably also the high) while significantly attenuating tolerance. Another found using normal doses of delta-receptor specific antagonist along with a regular (mu agonist) opioid did the same. Pretty neat....
NIDA Res Monogr 1995;147:53-83
Neuropsychopharmacology 13:347-356 (Dec 1995)
Pain 84:121-131 (Feb 2000)
JPET 295:1012-1021 (Dec 2000)
JPET 295:1142-1148 (Dec 2000)
If any of this research pans out and a simple, safe agent for blocking/reducing tolerance becomes available, it will be pretty sweet. Heroin addiction doesn't sound nearly as bad at $10 a day...
Care,
Zorn
[This message has been edited by zorn (edited 16 November 2001).]
Beta-arrestin-2
This is the most interesting and least practical approach. The opioid receptors are G protein coupled receptors (GPCRs); when an opioid binds to them, they release part of a special protein called a G protein into the cell, which does various other things that eventually cause the opioid's effects. After the G protein is released, the receptor is marked by an enzyme called G protein receptor kinase (GRK). Sometimes the receptor eventually gets a new G protein and can cause more opioid effects, and sometimes it gets stuck with something called an arrestin, which can disable it or haul it off to the receptor graveyard. Losing receptors this way is believed to be one of the mechanisms underlying the development of opioid tolerance.
The particular arrestin responsible for opioid receptors seems to be beta-arrestin-2. Some researchers recently made a strain of mice lacking the gene for this arrestin, and found that they were supersensitive to opioids -- 1mg/kg morphine corresponded to 5mg/kg in normal mice -- and developed no tolerance at all to opioids. Besides that they appeared perfectly normal. Strangely, the mice did get addicted, and went through withdrawal just like normal mice. The researchers got published in both Science and Nature for their work (the mice got to stay high for a couple weeks, then were killed.) Now if only I could get all my beta-arrestin destroyed....
Incidentally there are two phases of opioid tolerance: acute tolerance, which develops within minutes and fades in hours, and chronic tolerance, which develops and fades over days; the mice experienced neither. The timecourse of acute tolerance sounds suspiciously like that of the rush from i.v. opioids. I'd guess without acute tolerance the rush would wear off only very slowly. Now if only I could get all my beta-arrestin-2 destroyed...
Nature 2000 Dec 7;408(6813):720-3 http://www.nature.com/cgi-taf/DynaPage.taf?file=/natur e/journal/v408/n6813/abs/408720a0_fs.html&dynoptions=doi1005920490
Other stuff
NMDA antagonists (ketamine,DXM,PCP among others) attenuate opioid tolerance, no one seems sure how. Inhibitors of nitric oxide synthase seem to do the same thing. A new research drug involved with substance P system similarly blocks tolerance (see papers below).
Closer to clinical use are studies using opioid antagonists (eg naloxone), which are easily available and tested. One study found that very tiny doses of an antagonist along with an opioid maintained the analgesic ability (presumably also the high) while significantly attenuating tolerance. Another found using normal doses of delta-receptor specific antagonist along with a regular (mu agonist) opioid did the same. Pretty neat....
NIDA Res Monogr 1995;147:53-83
Neuropsychopharmacology 13:347-356 (Dec 1995)
Pain 84:121-131 (Feb 2000)
JPET 295:1012-1021 (Dec 2000)
JPET 295:1142-1148 (Dec 2000)
If any of this research pans out and a simple, safe agent for blocking/reducing tolerance becomes available, it will be pretty sweet. Heroin addiction doesn't sound nearly as bad at $10 a day...
Care,
Zorn
[This message has been edited by zorn (edited 16 November 2001).]
