Mechanism Based Neurotherapeutics for Osteoarticular Pain
Sponsored by The American Federation for Medical Research

Chronic joint pain represents a high prevalence disabling condition with an unmet need for effective treatment. Recent advances in our understanding of the molecular basis of the inhibitory effects of botulinum toxin on neuronal exocytosis, as well as the neurobiology of persistent osteoarticular pain are emerging with pre-clinical animal studies and initial clinical experience with intra-articular administration of botulinum toxin type A.  The convergence of notable progress in these basic and clinical science investigations presents a sound and attractive foundation for a timely discussion of interactive translation of basic research findings into clinical experience and back again back to the laboratory. 

BOTOX has proved extremely successful in the clinical treatment of conditions arising from over-active cholinergic nerves in the motor and autonomic nervous systems. This is due to its unique abilities – experimentally demonstrated in animal models – to a) target the nerves via binding to ecto-acceptors located exclusively thereon; b) undergo internalisation by acceptor-mediated endocyosis, and c) block acetylcholine release, thereby, inducing long-term muscle weakening due to proteolytic cleavage and disabling of a SNARE protein, SNAP-25, that is essential for transmitter release, Fortunately, when successfully delivered into other neuronal types, this highly potent neurotoxin can also inhibit the exocytosis of transmitters that mediate pain including those from small clear vesicles (e.g. glutamate) and large dense-core vesicles (e.g. peptides like cGRP, substance P). With the current availability in the Dolly lab of fully-active BoNT, produced by recombinant means, it is now feasible to exploit the proven technologies for re-targeting this novel protein to sensory nerve endings. This is an exciting new development in toxic science that should be exploited by close cooperation with clinical researchers. Such an advance would greatly improve the targeting specificity of this new therapeutic as well as raising its potency. As the unmodified BOTOX has already been shown to be effective in long-term control of chronic joint pain due to  knee and shoulder arthritis when administered directly into the affected site, the above-noted improvement ought to prove highly successful both as a research tool for studying the mechanisms of nocioception, and as a novel agent for treating chronic pain due to arthritis.