Originally Posted by meth
Any updates from ExD, EA, JB?
Only if you can stand me further derailing ExD's thread away from stim-induced bruxism to opiates.
I think one of the implicit lessons in that last batch of opiate sensitisation research which I posted was the differences at the cellular level between endogenous opioids and exogenous drugs. It wouldn't surprise me at all if something similar operates in the stims vs dopamine receptor field, although I haven't gone looking for that. However, things get even more complicated. Back on the subject of opiates, it turns out that there is a poorly-recognised view that morphine is actually an endogenous transmitter, and its actions aren't limited to the neural area but span the immune, vascular systems, and a few others. It's hard to find a paper on this topic without Stefano's name on it (which makes me a little wary), but it's all a well-written, provocative mix of results and conjecture. This next abstract gets us somewhat back onto the sensitisation track because it talks about morphine causing paradoxical hyperalgesia, and also drags in some links with NO and NMDA, as Epsilon previously mentioned:
Med Sci Monit. 2009 May;15(5):RA107-10.
Xenobiotic perturbation of endogenous morphine signaling: paradoxical opiate hyperalgesia.
Stefano GB, Esch T, Kream RM.
Source
Neuroscience Research Institute, State University of New York - College at Old Westbury, Old Westbury NY 11568, USA.
[email protected]
Abstract
The clinical literature has extensively documented diverse, potentially debilitating, side-effects of pharmaceutical dosages of morphine and morphine congeners administered for management of acute and chronic pain. Paradoxically, morphine is capable of engendering state-dependent hyperalgesic responses that appear to be functionally linked to secondary activation of N-methyl-D-aspartate (NMDA) receptors coupled to Ca++-evoked nitric oxide (NO) production. Similar biochemical events have been associated with the development of morphine tolerance. Recent lines of complementary evidence support both the existence and biological importance of cellular regulatory pathways mediated by endogenously synthesized, chemically authentic morphine. Cellular "morphinergic" signaling is mediated by cognate six-transmembrane helical domain (TMH) micro3 and micro4 opiate receptors linked to activation of constitutive NO synthase (cNOS). Based on the compelling association of both endogenous and exogenous morphine activation with enhanced NO production, we advance a hypothesis that morphine administered as a pharmaceutical/xenobiotic agent adversely perturbs normative "morphinergic"/NO signaling within discrete cellular microdomains. Accordingly, pharmaceutical and/or physiological disruption of basic metabolic events regulated by "morphinergic"/NO signaling is proposed to account for state-dependent morphine-mediated hyperalgesia, tolerance development, and related disruptive cellular adaptations.
PMID:19396050 [PubMed - indexed for MEDLINE]
Another interesting aspect of this endogenous morphine idea is that Stefano occasionally takes an evolutionary perspective and more or less argues that some transmitters are more fundamental than others, with dopamine and morphine said to have a close relationship. Here's just one abstract of a number of similar ones:
CNS Neurosci Ther. 2010 Jun;16(3):e124-37. doi: 10.1111/j.1755-5949.2009.00114.x. Epub 2009 Nov 13.
Dopamine, morphine, and nitric oxide: an evolutionary signaling triad.
Stefano GB, Kream RM.
Source
Neuroscience Research Institute, State University of New York-College at Old Westbury, USA.
[email protected] <
[email protected]>
Abstract
Morphine biosynthesis in relatively simple and complex integrated animal systems has been demonstrated. Key enzymes in the biosynthetic pathway have also been identified, that is, CYP2D6 and COMT. Endogenous morphine appears to exert highly selective actions via novel mu opiate receptor subtypes, that is, mu3,-4, which are coupled to constitutive nitric oxide release, exerting general yet specific down regulatory actions in various animal tissues. The pivotal role of dopamine as a chemical intermediate in the morphine biosynthetic pathway in plants establishes a functional basis for its expansion into an essential role as the progenitor catecholamine signaling molecule underlying neural and neuroendocrine transmission across diverse animal phyla. In invertebrate neural systems, dopamine serves as the preeminent catecholamine signaling molecule, with the emergence and limited utilization of norepinephrine in newly defined adaptational chemical circuits required by a rapidly expanding set of physiological demands, that is, motor and motivational networks. In vertebrates epinephrine, emerges as the major end of the catecholamine synthetic pathway consistent with a newly incorporated regulatory modification. Given the striking similarities between the enzymatic steps in the morphine biosynthetic pathway and those driving the evolutionary adaptation of catecholamine chemical species to accommodate an expansion of interactive but distinct signaling systems, it is our overall contention that the evolutionary emergence of catecholamine systems required conservation and selective "retrofit" of specific enzyme activities, that is, COMT, drawn from cellular morphine expression. Our compelling hypothesis promises to initiate the reexamination of clinical studies, adding new information and treatment modalities in biomedicine.
PMID:19912274 [PubMed - indexed for MEDLINE]
So what might be some practical implications here? Well, in light of the above, there are theories that persons deficient in either CYP2D6 or COMT could thus be deficient in endogenous morphine and therefore candidates for all sorts of mental problems, but the results aren't nearly as clear-cut as all that. But secondly, there's the idea of manipulating NO pathways as a means of preventing drug tolerance, withdrawal, etc (and, who knows, behavioural sensitisation)? I recall this idea received a bit of press around M&M, but here's just one abstract to refresh the collective memory:
Anesthesiology. 2009 Jan;110(1):166-81. doi: 10.1097/ALN.0b013e31819146a9.
Modulation of opioid actions by nitric oxide signaling.
Toda N, Kishioka S, Hatano Y, Toda H.
Source
Shiga University of Medical Science, Shiga, Japan.
[email protected]
Abstract
Nitric oxide (NO) plays pivotal roles in controlling physiological functions, participates in pathophysiological intervention, and is involved in mechanisms underlying beneficial or untoward actions of therapeutic agents. Endogenous nitric oxide is formed by three isoforms of nitric oxide synthase: endothelial, neurogenic and inducible. The former two are constitutively present mainly in the endothelium and nervous system, respectively, and the latter one is induced by lipopolysaccharides or cytokines mainly in mitochondria and glial cells. Constitutively formed nitric oxide modulates the actions of morphine and related analgesics by either enhancing or reducing antinociception. Tolerance to and dependence on morphine or its withdrawal syndrome are likely prevented by nitric oxide synthase inhibition. Information concerning modulation of morphine actions by nitric oxide is undoubtedly useful in establishing new strategies for efficient antinociceptive treatment and for minimizing noxious and unintended reactions.
PMID:19104184 [PubMed - indexed for MEDLINE]
Free full text
Note that there are are three forms of NO synthase, so any manipulations would have to be appropriately targetted. There has been some interest in the past regarding the use of agmatine as a so-called NMDA antagonist, whereas it is possibly more appropriately described as a NOS inhibitor. It used to be hellishly expensive, but I have noticed that NutraP have recently started carrying it for a more reasonable price. Could be worth a play ...
