Neurobiological basis for the use of botulinum toxin in pain therapy
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The various serotypes of botulinum toxin (BoNT) exert their action by inhibiting the exocytosis of acetylcholine (ACh) in cholinergic nerve endings. BoNT cleaves proteins (e. g. SNAP-25 or VAMP) that are necessary for the docking of the ACh vesicle to the presynaptic membrane. Without docking, no ACh can be released into the synaptic cleft and the innervated structure is paralyzed. This article focusses on the neuromuscular endplate.
The main targets of BoNT therapy are states of muscle hyperactivity such as contractures (in the physiological sense), or spasm and focal dystonias.
The “integrated hypothesis” of the formation of myofascial trigger points suggests that a lesion of a muscle damages the endplate so that excessive ACh is released. This causes a local contracture (partial contraction of a muscle fiber) underneath the endplate. The contracture compresses small blood vessels, and the tissue becomes ischemic. Ischemia leads to the release of bradykinin (BKN) and sensitization or excitation of nociceptors. BoNT is a causal therapy in these cases, because it stops the excessive ACh release.
Reflex spasm in a given muscle can be induced by nociceptive input from neighboring joints or muscles. If the force generated by a spasm is relatively high, it will compress the large blood vessels supplying the muscle. The final effect again is ischemia. In this case a drop in pH may accompany the ischemia and BKN release. Protons and BKN are known to be effective stimulants for muscle nociceptors.
In cases of weak dystonias, a compression of blood vessels is unlikely. However, the tonic contraction will cause a lowering of pH and a release of ATP. Muscle cells contain ATP at concentrations sufficient to excite muscle nociceptors. In cases of spasm and dystonia, BoNT can abolish the pain by relaxing the muscle.
Since many patients report alleviation of their pain before the muscle relaxing effect of BoNT has set in, a direct analgesic action of BoNT is being discussed. Most hypotheses rest on the assumption that BoNT inhibits not only the exocytosis of ACh but also of other neurotransmitters. Such an action could be analgesic if the release of neuropeptides from nociceptive nerve endings is prevented. This way, BoNT could alleviate the pain of neuropathies and various types of headache where neurogenic inflammation plays a role. Another site of an analgesic action could be the postganglionic sympathetic nerve ending that uses norepinephrine and ATP as transmitters. Norepinephrine is known to increase cases of chronic pain, and ATP is a stimulant of muscle nociceptors. If BoNT inhibits the release of these transmitters, it could be analgesic in cases of sympathetically maintained pain including the complex regional pain syndrome.