Another Toxin with Analgesic Properties

Toxin from the cobra known as Naja naja atra has analgesic effects. Caveat: these studies are on nociceptive (ordinary) pain models.

We never said the pain system was simple. Neither is pain relief. Fortunately, we will not have to wait until we understand pain in order to remediate it. If your roof if leaking, you can repair the hole without understanding weather. Here we review some of the information coming out on cobra toxins and show how they can differ from the expected.

As you well know by now from reading prior articles, one of the pain inhibitory areas of the brain is the periaqueductal gray (PAG). The PAG was traditionally thought to operate via the conventional pain inhibitory substances, GABA and glycine. These oppose the conventional pain excitatory substances, glutamate and aspartate. You can read about this using SEARCH at this site. About a year ago, we also published an article about work from Marshall Devor, who is a correspondent here, who discovered a pain inhibitory area in the rostral ventral medulla which operated using acetyl choline.

Thus, you should differentiate at least two broad areas in pain inhibition. One, which includes the PAG, is concerned with the chemistry of the two inhibitory amino acid derivatives, GABA and glycine. The second uses acetyl choline, and would therefore be referred to as a cholinergic pain inhibitory network. One must also consider whether the pain inhibition is being exerted in the central or peripheral nervous structures, and whether the pain is normal (nociceptive) or neuropathic (nerve injury) in nature.

At this point, we also define the term “receptin”. This is a general term for any microbial compound which can bind to mammalian proteins. Substances which bind to carbohydrates, on the other hand, are known as “lectins”.

Zhang et al reported in Neurosci Bull. 2006 Mar;22(2):103-9 that SHORT CHAIN alpha cobratoxin injected into the ventricles (cavities) of the brain caused marked analgesia in a nociceptive model involving a hot plate. The effect was most potent if the cobratoxin was injected directly into the periqueductal gray. Remember that the PAG surrounds the aqueduct which connects to the lower cerebral ventricles.

This pain relief was not associated with any opiate receptor effect as shown by the co treatment with naloxone, which blocks opiates. Unexpectedly, the co-administration of atropine, which blocks acetyl choline activity, DID show that the cholinergic system was involved, DESPITE the lead role of the PAG. This suggeests some mechanism by which the PAG interacts with cholinergic pain inhibition pathways, such as the one described by Marshall Devor.

Chen, with Zhang et al in Acta Pharmacol Sin. 2006 Apr;27(4):402-8, showed that
LONG CHAIN alpha neurotoxin from the cobra also caused analgesia. This toxin’s pain relief came on best at THREE HOURS after injection into the cerebral ventricles, suggesting it was traveling somewhere. However, injection into the PAG of this LONG CHAIN cobratoxin DID NOT cause analgesia. Again, the opiate system was not involved, since naloxone, an opiate blocker, had no effect on the study. The effect was deemed cholinergic.

You see the problem. Different pain inhibition pathways exist. Just to make life interesting Zhang et al at Neurosci Bull. 2006 Sep;22(5):267-73 also described a receptin, created by chemically modifying cobra toxin, which blocked pain, but did so by acting not on the central, but on peripheral pain inhibition pathways.

Zhang, this prolific Chinese researcher, also reported at Toxicon. 2006 Aug;48(2):175-82 that venom from another snake, Crotalus durissus terrificus, reduces pain to a lesser degree. This toxin was most potent when injected directly into the PAG, and studying mainly the muscarinic branch (see prior using SEARCH) of the autonomic nervous system, as well as opiate receptors, Zhang concluded that the cholinergic and opioid systems of pain inhibition were not involved.

And so here we see three studies, more or less mirroring each other which seem to both rule out and implicate the PAG in pain relief which is linked to acetyl choline. Acetyl choline of course can be both an activator and inhibitor in the nervous system. It is a neurotransmitter, but the end result is dependant on the nature of the receptor activated, NOT the activating neurotransmitter. The picture is complex. We are glad the Chinese are involved in threading out pain inhibition pathways. They seem to be doing an admirable job.