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Current status and future directions of botulinum neurotoxins for targeting pain processing.

Pellett S, Yaksh TL, Ramachandran R - Toxins (Basel) (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Bacteriology, University of Wisconsin, 6340 Microbial Sciences Building, 1550 Linden Dr., Madison, WI 53706, USA. sabine.pellett@wisc.edu.

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.

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Related in: MedlinePlus

Schematics of possible mechanisms of action of peripherally applied BoNT/A1 and /B1 upon nociceptive processing: (A) Periphery: (1) At the site of injection BoNTs are endocytosed into the local peripheral afferents, where they cleave SNAREs, thereby inhibiting vesicular fusion and exocytosis of neurotransmitters. This in turn would block vasodilation, plasma extravasation, and activation local inflammatory cells. (2) BoNTs may also regulate SNARE-mediated cell surface expression of a variety of receptors and channels implicated in peripheral sensitization (e.g., TRPV1). (3) Another hypothesis is that BoNTs may enter local resident cells (e.g., mast cells) or migrating cells (e.g. neutrophils) otherwise evoked by injury or inflammation and may directly block the release of cytokines or pro-inflammatory molecules. These release products can activate and sensitize local small afferent terminals. (B) Spinopetal transport: (4) Following endocytosis in the peripheral terminals, some of the BoNT appears to undergo retrograde transport along the axon. (5) These transported BoNTs reach the dorsal root ganglion (DRG) neuron and cleave SNAREs in the DRG neurons to block vesicular release of neurotransmitters into the extracellular milieu of the DRG, which would otherwise activate and (6) excite the neighboring sensory neurons or (7) closely associated satellite cells. (8) BoNT may further undergo intra-vesicular axonal trafficking to the central terminals, where again by truncating respective SNAREs, it would inhibit neurotransmitter release, thereby preventing the activation of second order neurons and neighboring glial cells. (C) Trans-synaptic actions: BoNTs can undergo long axonal transport in intact form in non-acidic endosomes and may possibly undergo transcytosis centrally either to the (9) second order neurons or (10) glial cells. Activated glial cells release a plethora of pro-algesic substances (cytokines, chemokines, lipids, amino acids) serving to initiate and maintain central sensitization. (11) BoNTs may also get transcytosed to excitatory (glutamatergic) or inhibitory (GABA/glycinergic) interneurons and may act to block their neurotransmitter release resulting in a loss of excitatory drive or inhibitory control, respectively). Cleaved SNAREs in the second order neurons may interfere with fusion of endosomes that carry the receptors to the membrane. (12) Though speculative, if there is transcytosis to second order projection neurons, it is a reasonable hypothesis that these BoNT are transported to distal terminals which lie in the brainstem and further block the neurotransmission into the brainstem and higher centers.
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toxins-07-04519-f003: Schematics of possible mechanisms of action of peripherally applied BoNT/A1 and /B1 upon nociceptive processing: (A) Periphery: (1) At the site of injection BoNTs are endocytosed into the local peripheral afferents, where they cleave SNAREs, thereby inhibiting vesicular fusion and exocytosis of neurotransmitters. This in turn would block vasodilation, plasma extravasation, and activation local inflammatory cells. (2) BoNTs may also regulate SNARE-mediated cell surface expression of a variety of receptors and channels implicated in peripheral sensitization (e.g., TRPV1). (3) Another hypothesis is that BoNTs may enter local resident cells (e.g., mast cells) or migrating cells (e.g. neutrophils) otherwise evoked by injury or inflammation and may directly block the release of cytokines or pro-inflammatory molecules. These release products can activate and sensitize local small afferent terminals. (B) Spinopetal transport: (4) Following endocytosis in the peripheral terminals, some of the BoNT appears to undergo retrograde transport along the axon. (5) These transported BoNTs reach the dorsal root ganglion (DRG) neuron and cleave SNAREs in the DRG neurons to block vesicular release of neurotransmitters into the extracellular milieu of the DRG, which would otherwise activate and (6) excite the neighboring sensory neurons or (7) closely associated satellite cells. (8) BoNT may further undergo intra-vesicular axonal trafficking to the central terminals, where again by truncating respective SNAREs, it would inhibit neurotransmitter release, thereby preventing the activation of second order neurons and neighboring glial cells. (C) Trans-synaptic actions: BoNTs can undergo long axonal transport in intact form in non-acidic endosomes and may possibly undergo transcytosis centrally either to the (9) second order neurons or (10) glial cells. Activated glial cells release a plethora of pro-algesic substances (cytokines, chemokines, lipids, amino acids) serving to initiate and maintain central sensitization. (11) BoNTs may also get transcytosed to excitatory (glutamatergic) or inhibitory (GABA/glycinergic) interneurons and may act to block their neurotransmitter release resulting in a loss of excitatory drive or inhibitory control, respectively). Cleaved SNAREs in the second order neurons may interfere with fusion of endosomes that carry the receptors to the membrane. (12) Though speculative, if there is transcytosis to second order projection neurons, it is a reasonable hypothesis that these BoNT are transported to distal terminals which lie in the brainstem and further block the neurotransmission into the brainstem and higher centers.

Mentions: There is strong and diverse evidence that, as shown in Figure 3, locally delivered BoNTs can be taken up in the terminal of the sensory afferent, and local effects exerted by this toxin will be considered below.


Current status and future directions of botulinum neurotoxins for targeting pain processing.

Pellett S, Yaksh TL, Ramachandran R - Toxins (Basel) (2015)

Schematics of possible mechanisms of action of peripherally applied BoNT/A1 and /B1 upon nociceptive processing: (A) Periphery: (1) At the site of injection BoNTs are endocytosed into the local peripheral afferents, where they cleave SNAREs, thereby inhibiting vesicular fusion and exocytosis of neurotransmitters. This in turn would block vasodilation, plasma extravasation, and activation local inflammatory cells. (2) BoNTs may also regulate SNARE-mediated cell surface expression of a variety of receptors and channels implicated in peripheral sensitization (e.g., TRPV1). (3) Another hypothesis is that BoNTs may enter local resident cells (e.g., mast cells) or migrating cells (e.g. neutrophils) otherwise evoked by injury or inflammation and may directly block the release of cytokines or pro-inflammatory molecules. These release products can activate and sensitize local small afferent terminals. (B) Spinopetal transport: (4) Following endocytosis in the peripheral terminals, some of the BoNT appears to undergo retrograde transport along the axon. (5) These transported BoNTs reach the dorsal root ganglion (DRG) neuron and cleave SNAREs in the DRG neurons to block vesicular release of neurotransmitters into the extracellular milieu of the DRG, which would otherwise activate and (6) excite the neighboring sensory neurons or (7) closely associated satellite cells. (8) BoNT may further undergo intra-vesicular axonal trafficking to the central terminals, where again by truncating respective SNAREs, it would inhibit neurotransmitter release, thereby preventing the activation of second order neurons and neighboring glial cells. (C) Trans-synaptic actions: BoNTs can undergo long axonal transport in intact form in non-acidic endosomes and may possibly undergo transcytosis centrally either to the (9) second order neurons or (10) glial cells. Activated glial cells release a plethora of pro-algesic substances (cytokines, chemokines, lipids, amino acids) serving to initiate and maintain central sensitization. (11) BoNTs may also get transcytosed to excitatory (glutamatergic) or inhibitory (GABA/glycinergic) interneurons and may act to block their neurotransmitter release resulting in a loss of excitatory drive or inhibitory control, respectively). Cleaved SNAREs in the second order neurons may interfere with fusion of endosomes that carry the receptors to the membrane. (12) Though speculative, if there is transcytosis to second order projection neurons, it is a reasonable hypothesis that these BoNT are transported to distal terminals which lie in the brainstem and further block the neurotransmission into the brainstem and higher centers.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663519&req=5

toxins-07-04519-f003: Schematics of possible mechanisms of action of peripherally applied BoNT/A1 and /B1 upon nociceptive processing: (A) Periphery: (1) At the site of injection BoNTs are endocytosed into the local peripheral afferents, where they cleave SNAREs, thereby inhibiting vesicular fusion and exocytosis of neurotransmitters. This in turn would block vasodilation, plasma extravasation, and activation local inflammatory cells. (2) BoNTs may also regulate SNARE-mediated cell surface expression of a variety of receptors and channels implicated in peripheral sensitization (e.g., TRPV1). (3) Another hypothesis is that BoNTs may enter local resident cells (e.g., mast cells) or migrating cells (e.g. neutrophils) otherwise evoked by injury or inflammation and may directly block the release of cytokines or pro-inflammatory molecules. These release products can activate and sensitize local small afferent terminals. (B) Spinopetal transport: (4) Following endocytosis in the peripheral terminals, some of the BoNT appears to undergo retrograde transport along the axon. (5) These transported BoNTs reach the dorsal root ganglion (DRG) neuron and cleave SNAREs in the DRG neurons to block vesicular release of neurotransmitters into the extracellular milieu of the DRG, which would otherwise activate and (6) excite the neighboring sensory neurons or (7) closely associated satellite cells. (8) BoNT may further undergo intra-vesicular axonal trafficking to the central terminals, where again by truncating respective SNAREs, it would inhibit neurotransmitter release, thereby preventing the activation of second order neurons and neighboring glial cells. (C) Trans-synaptic actions: BoNTs can undergo long axonal transport in intact form in non-acidic endosomes and may possibly undergo transcytosis centrally either to the (9) second order neurons or (10) glial cells. Activated glial cells release a plethora of pro-algesic substances (cytokines, chemokines, lipids, amino acids) serving to initiate and maintain central sensitization. (11) BoNTs may also get transcytosed to excitatory (glutamatergic) or inhibitory (GABA/glycinergic) interneurons and may act to block their neurotransmitter release resulting in a loss of excitatory drive or inhibitory control, respectively). Cleaved SNAREs in the second order neurons may interfere with fusion of endosomes that carry the receptors to the membrane. (12) Though speculative, if there is transcytosis to second order projection neurons, it is a reasonable hypothesis that these BoNT are transported to distal terminals which lie in the brainstem and further block the neurotransmission into the brainstem and higher centers.
Mentions: There is strong and diverse evidence that, as shown in Figure 3, locally delivered BoNTs can be taken up in the terminal of the sensory afferent, and local effects exerted by this toxin will be considered below.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Bacteriology, University of Wisconsin, 6340 Microbial Sciences Building, 1550 Linden Dr., Madison, WI 53706, USA. sabine.pellett@wisc.edu.

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.

Show MeSH
Related in: MedlinePlus