Limpet_Chicken
Bluelighter
- Joined
- Oct 13, 2005
- Messages
- 6,323
Doing some research, it seems like there is a peptide binding site on filamin A, that acts as a high affinity binding site for naltrexone, and seems to regulate tolerance, I could do with finding more on this though.
Also, there appear to be two very distinct populations of the opioid receptor in question. First, there are Mu1 and Mu2, also Mu3 (this appears to be coupled to NO production, and possibly have little to do with pain regulation or euphoria, although its activated by morphine and opiate alkaloids but is insensitive to peptidic agonists like DAMGO, and the like.
Mu1 is the one that is responsible, primarily, as I understand it, for euphoric effects (there are some 15 splice variants in the human MOR1 gene, of interest, I'll throw in that some derivatives of naltrexone have been shown to be splice variant-specific, for the exon 11 splice variant, is iodobenzoylnaltrexamide for instance, this appears to lack reinforcing and possibly euphorigenic properties, but likewise, most of the side effects such as constipation, respiratory depression, dependence, tolerance formation)
MOR2 also mediates pain relief IIRC, to a degree, but is also expressed in the gut, and agonism here results in respiratory depression and inhibition of G.I tract motility.
There appear to be distinct populations of MOR1, a high affinity subtype of excitatory nature, and a lower affinity subtype which produces the well known, and sought after characteristic effects of MOR1 agonists in vivo. Not sure what the other population do when activated.
Naltrexone is known to inhibit a switch in G-protein association (MOR, is a 7-transmembrane G-protein coupled receptor, or 6-TM-GCPR in the case of some of the known truncated splice variants), from the inhibitory GαI/o coupling (leading via intracellular effectors to a decrease in cAMP formation) to the excitatory GαS and possibly Gβγ heterodimers, this switch with tolerance and continued use of opioid agonists seems to trigger a switch from analgesic, to promotion of hyperalgesia and allodynia-obviously this does not occur with all isoforms of the hMOR, else we would see a complete switch eventually from the effects we seek to pain causing with continued use, outside the context of withdrawal, would we not? At any rate, analgesia seems to be one of the last to go, as far as Mu1-OR mediated opioid effects go.
I read an interesting paper just tonight, sorry I can't post the link right now, its a paper print, but it shows at least in the murine conditioned place avoidance/preference testing paradigm, that oxycodone, and morphine ? the controlled place preference graph corresponding to morphine just has single paired bar graphs for morphine/saline and morphine/NTX) exhibited a biphasic response to ultra low dose NTX, with the lowest levels, the very lowest tested (5mg/kg morphine used in all cases bar placebo control, dose of oxy 3mg/kg), I find this very interesting, and wonder if it holds true for morphine also. Oxycodone at 3mg/kg produced CPP that was VERY dramatically blocked by 0.003 ng/kg (damn....so this high affinity binding site must bind naltrexone with at least picomolar affinity.), this increased CPP at 0.3ng/kg, still further at 3ng/kg and interestingly again, time spent in the active drug (vs saline) compartment of the testing chamber by the rats dropped down but produced only place-preference conditioning again, forming a bell curve.
Psychopharmacology (2005) 181: 576-581
DOI 10.1007/s00213-005-005-0022-7
ultra low dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats.
I'll have to try and find the other paper again, but this was something I dug up off the wayback machine called 'naltrexone trial diary' from dilaudid.net, about a guy doing some practical trials ala Ott, with dose titration etc.
Un-be-fucking-lievable! guy was taking some 40-50mg of hydromorphone a day, and more, yet managed to get down to a state where 8mg per os flattened him. Look for it people, I'm not sure if I have the address saved or could find it again, I only have a paper copy.
Also, there appear to be two very distinct populations of the opioid receptor in question. First, there are Mu1 and Mu2, also Mu3 (this appears to be coupled to NO production, and possibly have little to do with pain regulation or euphoria, although its activated by morphine and opiate alkaloids but is insensitive to peptidic agonists like DAMGO, and the like.
Mu1 is the one that is responsible, primarily, as I understand it, for euphoric effects (there are some 15 splice variants in the human MOR1 gene, of interest, I'll throw in that some derivatives of naltrexone have been shown to be splice variant-specific, for the exon 11 splice variant, is iodobenzoylnaltrexamide for instance, this appears to lack reinforcing and possibly euphorigenic properties, but likewise, most of the side effects such as constipation, respiratory depression, dependence, tolerance formation)
MOR2 also mediates pain relief IIRC, to a degree, but is also expressed in the gut, and agonism here results in respiratory depression and inhibition of G.I tract motility.
There appear to be distinct populations of MOR1, a high affinity subtype of excitatory nature, and a lower affinity subtype which produces the well known, and sought after characteristic effects of MOR1 agonists in vivo. Not sure what the other population do when activated.
Naltrexone is known to inhibit a switch in G-protein association (MOR, is a 7-transmembrane G-protein coupled receptor, or 6-TM-GCPR in the case of some of the known truncated splice variants), from the inhibitory GαI/o coupling (leading via intracellular effectors to a decrease in cAMP formation) to the excitatory GαS and possibly Gβγ heterodimers, this switch with tolerance and continued use of opioid agonists seems to trigger a switch from analgesic, to promotion of hyperalgesia and allodynia-obviously this does not occur with all isoforms of the hMOR, else we would see a complete switch eventually from the effects we seek to pain causing with continued use, outside the context of withdrawal, would we not? At any rate, analgesia seems to be one of the last to go, as far as Mu1-OR mediated opioid effects go.
I read an interesting paper just tonight, sorry I can't post the link right now, its a paper print, but it shows at least in the murine conditioned place avoidance/preference testing paradigm, that oxycodone, and morphine ? the controlled place preference graph corresponding to morphine just has single paired bar graphs for morphine/saline and morphine/NTX) exhibited a biphasic response to ultra low dose NTX, with the lowest levels, the very lowest tested (5mg/kg morphine used in all cases bar placebo control, dose of oxy 3mg/kg), I find this very interesting, and wonder if it holds true for morphine also. Oxycodone at 3mg/kg produced CPP that was VERY dramatically blocked by 0.003 ng/kg (damn....so this high affinity binding site must bind naltrexone with at least picomolar affinity.), this increased CPP at 0.3ng/kg, still further at 3ng/kg and interestingly again, time spent in the active drug (vs saline) compartment of the testing chamber by the rats dropped down but produced only place-preference conditioning again, forming a bell curve.
Psychopharmacology (2005) 181: 576-581
DOI 10.1007/s00213-005-005-0022-7
ultra low dose naltrexone suppresses rewarding effects of opiates and aversive effects of opiate withdrawal in rats.
I'll have to try and find the other paper again, but this was something I dug up off the wayback machine called 'naltrexone trial diary' from dilaudid.net, about a guy doing some practical trials ala Ott, with dose titration etc.
Un-be-fucking-lievable! guy was taking some 40-50mg of hydromorphone a day, and more, yet managed to get down to a state where 8mg per os flattened him. Look for it people, I'm not sure if I have the address saved or could find it again, I only have a paper copy.
)...but when something needs working out on a deadline, I SO shouldn't be trying to figure all this out right now..but damn it, You got me interested in the zeta opioid growth factor receptors again.