Noscapine

Noscapine  is  found in the Opium poppy.

It is without significant painkilling properties, but has some extremely interesting properties of its own, which are due to its effects on other receptors. It is non-addictive and has ‘a low side-effect incidence’.  But it does have a history of ‘abuse’, as it is euphemistically called, meaning it has some properties which might contribute to opium’s rather unique overall profile.

At the moment there appears to be some disagreement [from what I can judge from research papers] on which receptor or action specifically gives Noscapine its antitussive properties. There does seem to be agreement that it is not opioid receptors – “the antitussive effect of noscapine is not mediated via the mu, kappa or delta opioid receptors”.  Despite the conclusions of the paper above, the three candidates for its action are [and they don’t need to be exclusive] the  Bradykinin (BK) receptors,  the sigma receptors and tubulin binding.

The tubulin theory – the first theory is based on the findings that Noscapine seems to display ‘tubulin-binding properties’.  Anything that binds to these receptors is anti-inflammatory.  Now since inflammation also causes pain, this would imply that Noscapine helps in pain relief by being an anti-inflammatory.  And it would also help a great deal in preventing coughing, as it is the inflammation that induces the cough – trying to get rid of the irritant.  Some analogues of Noscapine “ demonstrated anti-inflammatory properties in both TLR- and non-TLR induced in vitro innate immune pathway inflammation models, mimicking septic and sterile infection respectively”.  As they proudly said “This study is the first report to identify brominated noscapines as innate immune pathway anti-inflammatory molecules”.

The Bradykinin theory – the second theory is based on the hypothesis that noscapine has a specific antagonistic effect on Bradykinin (BK) receptors and ‘the mode of inhibition was found to be non-competitive’.  But the tests were done on guineau pigs [real guineau pigs not human guineau pigs].  The findings stated “Contractions of the isolated ileum of the guinea-pig in response to BK were inhibited by noscapine in a concentration-dependent manner”.  Now the ileum is the final section of the small intestine – so these tests are not very conclusive, if it had been a test of lung tissue, it may have been more compelling.  All this may prove is that noscapine has an effect on gut spasms.
Neverthless, Bradykinin is thought to be the cause of the dry cough in some patients on angiotensin converting enzyme (ACE) inhibitor drugs.  So any antagonist might have the effect of suppressing any dry cough.  And in stroke patients, noscapine appeared to block the bradykinine b-2 receptors. A 2003 study in Iran showed a dramatic decrease in mortality in patients treated with noscapine. 
Bradykinin also raises internal calcium levels in neocortical astrocytes causing them to release glutamate.   If it is an antagonist it will also have an effect on the glutamate receptors – it will be a GABA agonist.

The sigma receptor theory - In yet another study,  “Antitussive effects of noscapine were significantly and dose-dependently reduced by pretreatment with rimcazole, a specific antagonist of sigma sites. These results suggest that sigma sites may be involved in the antitussive mechanism of non-narcotic antitussive drug.   It also suggests that noscapine may be a sigma agonist. ”
I think the results here are also not conclusive.   “An increasing body of evidence suggests that the sigma receptor may be unique, in that it may modify synaptic transmission through the regulation of other  neurotransmitter receptors.  Thus, sigma receptor ligands may modulate glutamate and dopamine release”
So in reality, there may be an action via the sigma, but the main action is on the GABAA receptor.  It would also appear that the action is as an agonist.
Whichever route you take – vai Bradikinin or via the sigma route – and as I mentioned both may be involved because the pathways are quite complex – the end result is GABA agonism

The ‘anaesthetic’ effect – the NMDA antagonist

The common denominator of neuropathic pain seems to involve an over-activation of the  glutamate receptor subtype, termed the NMDA receptor.  Noncompetitive NMDA antagonists like MK-801 are potent inhibitors of neuropathic pain in all animal models tested ; however, only a few have been exposed to clinical trials. The main reason for this are, that it produces “severe psychotomimetic side-effects”.
Now any drug with psychotomimetic actions mimics the symptoms of psychosis, including delusions and/or hallucinations. Psychotomimetic drugs are also referred to as psychedelic or hallucinogenic drugs .  So any NMDA antagonist is by definition an hallucinogenic drug or a psychedelic.
The weaker noncompetitive NMDA receptor antagonists do not seem to produce the severe side-effects observed of some NMDA antagonists.
And it has been found that indeed Noscapine, is a weak noncompetitive NMDA receptor antagonist.
Note that there is a paper written by vets who found it is not an NMDA antagonist on rats [they used the spinal cord] and this has led to the general belief that Noscapine has no NMDA activity.  Other papers by anaesthetists however, using brain cells indicate that it has, I go with the anaesthetists on this because the side effects  tend to point to this being the case.

The anti-cancer effects

Noscapine has been seen to speed up autophagy.  Autophagy  is the process whereby the components and  molecules of a cell are broken down into smaller units and their energy released.   It is the body’s natural process of decay and recycling.  It plays a normal part in cell growth, development, and cell death, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products. The most well-known mechanism of autophagy involves the formation of a membrane around a targeted region of the cell, separating the contents from the rest of the cytoplasm. The contents are then acted upon.
In some cases the body uses it to fight off cell proliferation leading to cancer, but of course speed up the process on perfectly good cells and you have rather unknown results.   A number of people are getting quite excited about the possibility of using noscapine as an anti-cancer drug, quote
“In recent years, noscapine’s anti-cancer effect has been demonstrated when taken at doses higher than those used for cough suppression. It is currently in off-label use by a number of physicians in treatment of cancers of the breast, lung, prostate, ovaries and brain, and lymphomas, to name but a few. It is being clinically studied in non-Hodgkin’s lymphoma and chronic lymphocytic leukemia (CLL)”
I won’t get involved in this debate, but suffice it to say that in the healthy person with no cancer, its effects may be rather unpredictable.

In summary

What conclusions can we come to?  Nothing absolutely definite and that may be a problem.  Noscapine is an anti-inflammatory, anti-tussive [with help given for asthmatic irritant induced  coughs].  It has hallucinogen or psychedelic effects at sufficiently high doses that at those doses may cause degradation of cells.