Opioids Reduce Glutamate and Imatinib Reduces Opioid Tolerance.

Remy

Administrator
This is the weirdest thing...I had the WORST ear infection last week and I was prescribed codeine for the pain. I've noted previously that opiates were about the only medication I've ever taken that made me feel better and didn't cause horrible side effects or withdrawal. There was a whole long thread on PR about others who felt the same way. Unfortunately, this is a fairly unsustainable path due to the current opiate climate and prescribing regulations.

I took opiates on and off at a fairly low dose for many years after a terrible accident. They kept me going for nearly a decade but were unable to stop the crash of 2009 that put me into bedbound/housebound state. So I stopped taking them at that point.

I always thought they worked on dopamine and endorphin pathways...but I've been looking again and it seems like there is actually activity against glutamate at work. Could this be more responsible for the positive effects than the dopaminergic pathways? Or maybe some delicate interaction between glutamate, GABA and dopamine?

This blog touches on this topic:

The article also investigates the signal transduction pathways which are responsible for opioid addiction.

The release of calcium ions upon activation of the NMDA receptor leads to many different effects on the cell which all create withdrawal symptoms if the NMDA receptor is overstimulated.

Another important pathway to consider is that of protein kinase C which upon the increase in the calcium concentration in the cell, the kinase promotes the creation of copies of itself and phosphorylates, that is attaches a phosphate to a G-protein which leads to desensitization when the G-protein in question is on an opioid receptor.

Another important pathway to consider is the CREB pathway which is a common factor in many other cases of physical and psychological dependence. The application of opioids increases the concentration of CREB and related proteins and causes the copying of new proteins and leads to addiction.

Lastly, the MAP kinase pathway which is important in rewarding response and behavioral sensitization which is brought on by the administration of psychostimulants.

The interaction of glutamate with other neurotransmitters was also explored in this article. It is said in the article that there is an interaction between opioid receptors and glutamate receptors which is vital to opioid dependence.

It is also shown that there is a connection between glutamate and dopamine as it is shown that glutamate increases the amount of dopamine in NAc and increases the activity of dopaminergic neurons.

It is also shown that activation of opioid receptors in the brain inhibited the activity of GABA neurons and inhibited the chemicals release. GABA normally inhibits dopamine, so the result of the opioid application is the increase of dopamine in the system.
Quite a few things in those paragraphs caught my attention...but the biggest ones are the release of calcium ions (I've long agreed with those who think that MECFS may be a cause or result of aberrant calcium ion signaling. Mast cell issues may be caused or aggravated by high intracellular calcium levels also) and the mention of phosphorylation.

If you read the review I wrote of Dr Afrin's mast cell book, mention is made of a class of drugs called tyrosine kinase inhibitors which seem to have returned some people with MCAS to a near normal state of life.

Imatinib (Gleevec) is the name of one such tyrosine kinase inhibitor. And strangely enough, it has a "Major" interaction warning with hydrocodone. I at first assumed that must be due to interactions with the CYP system causing it to increase the levels. Maybe that is true as well...but look at this super interesting study from the MD Anderson Cancer Center...

They are using imatinib along with morphine to REVERSE opioid tolerance without affecting the pain relieving effects! So maybe the interaction doesn't actually have as much to do with CYP after all if they are using them together to make pain meds work better at lower doses...

Here's the report:

The development of tolerance to the analgesic effects of opioids limits effective treatment of chronic pain, and many labs are working to unravel the molecular mechanisms underlying morphine tolerance.

A study by Howard Gutstein and colleagues at the MD Anderson Cancer Center, Houston, US, demonstrates that in rats, morphine induces tolerance through a novel pathway involving activation of the platelet-derived growth factor receptor-β (PDGFR-β).

They go on to show that a widely used cancer drug, the PDGFR kinase inhibitor imatinib (Gleevec), eliminates morphine tolerance, without altering the drug's pain-killing ability. If the same holds true in people, imatinib may offer a new approach to the management of opioid tolerance in chronic pain.

The work was published online February 19 in Nature Medicine.

Restoration of power
Morphine is commonly used for the treatment of patients with severe pain. However, patients receiving morphine, or other opioids, often develop tolerance to the analgesic effects of the drugs. They require higher and higher doses of the drug until escalating side effects dictate the abandonment of therapy.

Previous research has yielded promising pharmacological targets to prevent or reverse tolerance, such as the NMDA-type glutamate receptor (NMDAR). However, therapeutics targeted toward dampening the NMDAR pathway have yet to yield promising results in humans.

Previous studies had shown that opioids activate receptor tyrosine kinases such as the PDGFR and the epidermal growth factor receptor (Belcheva et al., 2001; Chen et al., 2006), but the physiological role of this activation was unknown.

In the new study, Gutstein and colleagues found that morphine stimulated PDGFR-β phosphorylation in the spinal cords of rats, and that the phosphorylation could be blocked by imatinib, an FDA-approved inhibitor of the PDGF receptor tyrosine kinase.

They went on to show that treating rats with imatinib delivered into the spinal cord prevented the development of morphine tolerance as measured by the tail flick pain response, and reversed established tolerance without affecting the opioid’s analgesic effects.

Further studies established that morphine treatment stimulated tolerance via a novel pathway that was independent of NMDA receptors, and involved release of PDGF-β and subsequent receptor activation and phosphorylation. Administration of PDGF was sufficient to induce morphine tolerance in animals that had never been given opioids previously, the researchers showed.

Clinical formulations of imatinib do not cross the blood-brain barrier, so the authors used an FDA-approved vehicle to reformulate the drug to improve brain penetration. Using the new version, they found that subcutaneous administration of imatinib to rats reversed established tolerance to daily doses of morphine, or to constant infusion of high-dose morphine. The results suggested that imatinib could potentially be used as an adjunct therapy, as needed, to limit or reverse tolerance.

Despite the promise of imatinib as a potential therapeutic for pain, the current results reflect a small, preliminary study in rodents, and the potential for managing pain in humans has yet to be determined.

“If it works clinically, [imatinib] would be wonderful news for people who are trapped in the difficult choice between living with chronic pain or escalating their doses of opiates and struggling with their increasing side effects,” said Huda Akil, an opioid researcher at the University of Michigan, Ann Arbor, US, who was not involved with the study.

“This discovery is ripe for moving to the next stage of human testing, and exemplifies translational research at its very best,” said Akil.

Gutstein said his lab is now carrying out neurotoxicity studies to evaluate the effects of imatinib on the central nervous system. They hope to get results within the year, and that they can then pursue continued development of imatinib. The lab has no financial ties to Novartis, the maker of imatinib, he said.

Science motivated by passion
Gutstein didn't begin his career with an interest in research, he told PRF. He is a pediatric anesthesiologist, and in the clinic he saw patients who were terminally ill, in pain, and tolerant to morphine. His work has been motivated by witnessing harrowing scenes created by the inability to manage severe pain. “Sometimes I had to use general anesthesia with the kids at the end of life,” he said, because there was nothing else that would effectively treat their pain. “I had to do something to make things better for those kids.”

The publication of the imatinib results comes at a poignant time for Gutstein and colleagues, as the lead postdoctoral researcher on the project, Bing Mo, died of liver cancer while the work was being completed. The manuscript is dedicated to his memory.

Sonya Jakawich received her Ph.D. in Neuroscience from the University of Michigan, and when she isn’t writing about science, she can be found climbing in the White Mountains of New Hampshire.
REFERENCES:
Editors' Pick
Blockade of PDGFR-β activation eliminates morphine analgesic tolerance.
Wang Y, Barker K, Shi S, Diaz M, Mo B, Gutstein HB
Nat Med. 2012 Mar; 18(3):385-7. Epub 2012 Feb 19.
I can't quite tie it all together yet but it's really interesting to me. There are literally thousands of drugs...what are the odds of imatinib coming up here AND in MCAS?
 

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