Abstract
Current evidence suggests that botulinum neurotoxins (BoNTs) A1 and B1, given locally into peripheral tissues such as skin, muscles, and joints, alter nociceptive processing otherwise initiated by inflammation or nerve injury in animal models and humans. Recent data indicate that such locally delivered BoNTs exert not only local action on sensory afferent terminals but undergo transport to central afferent cell bodies (dorsal root ganglia) and spinal dorsal horn terminals, where they cleave SNAREs and block transmitter release. Increasing evidence supports the possibility of a trans-synaptic movement to alter postsynaptic function in neuronal and possibly non-neuronal (glial) cells. The vast majority of these studies have been conducted on BoNT/A1 and BoNT/B1, the only two pharmaceutically developed variants. However, now over 40 different subtypes of botulinum neurotoxins (BoNTs) have been identified. By combining our existing and rapidly growing understanding of BoNT/A1 and /B1 in altering nociceptive processing with explorations of the specific characteristics of the various toxins from this family, we may be able to discover or design novel, effective, and long-lasting pain therapeutics. This review will focus on our current understanding of the molecular mechanisms whereby BoNTs alter pain processing, and future directions in the development of these agents as pain therapeutics.
Highlights
Botulinum Neurotoxins (BoNTs) are the most potent toxins known to humankind and are the causative agent of the serious and potentially fatal paralytic disease botulism [1]
Spinal systems in the face of ongoing high frequency small afferent activation can display an enhanced input-output function, referred to as wind up and/or central sensitization [101,108]. The pharmacology of this central facilitation is complex and reflects: i) a progressive depolarization of the second order neuron; ii) activation of spinal kinases that enhance the reactivity of the second order membrane by phosphorylating membrane channels and receptors [109,110,111]; iii) changes in the transport of various excitatory receptor and channel subunits to the membrane [112,113,114], and iv) activation of dorsal horn non-neuronal cells leading to release of a variety of pro excitatory products [115,116]
The specificity of these effects on the role played by the cleavage of SNAREs was provided by two observations: i) intrathecal delivery of botulinum neurotoxins (BoNTs)/B1 treated with dithiotreitol to cleave the disulfide linkages had no activity, and ii) intrathecal BoNT/B1 serotype blocked formalin-evoked flinching in the mouse but not in the rat, an observation consistent with the fact that the rat VAMP1 has a mutation at the
Summary
Botulinum Neurotoxins (BoNTs) are the most potent toxins known to humankind and are the causative agent of the serious and potentially fatal paralytic disease botulism [1]. About 35–40 years ago, it was shown that local intramuscular injection of low doses of BoNTs resulted in local, long-lasting, but reversible paralysis of the injected muscle [2,3] This property of BoNTs proved useful for treatment of strabismus [3,4]. Common to all of these applications is that the BoNTs are taken up into the motor neuron terminal at the neuromuscular junction or parasympathetic axon terminal, where the toxin acts to block the release of acetylcholine [8] These effects are consistently achieved by a localized action after local delivery without systemic redistribution [2,3,4]. BoNT/A1 and /B1 in altering cellular function, ii) the effects of BoNT/A1 and /B1 on pain behavior phenotypes in preclinical models and in human pain states, iii) the likely mechanisms underlying this action and iv) future directions for the development of novel BoNT-based therapeutics to target nociceptive processing, and the value of investigating the diversity of the large family of BoNTs in this endeavor
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