Today's post from painresearchforum.org (see link below) looks at an issue that fascinates almost everyone from scientists to patients alike and that is whether Botox can help reduce neuropathic pain in humans. It was found that Botox can have a positive effect on people suffering from migraines but despite extensive research, the scientists can't establish why. However, extrapolating the science, it seems that Botox injected elsewhere in the body may have an equally beneficial effect on painful peripheral nerves - hence the hope that it can help people living with neuropathy. There have been whispers for years about Botox being a possible treatment but it has never translated to mainstream medical thinking. Now it looks as though it at least needs to be taken seriously as an option. You may need a dictionary of modern molecular biology to read this article (nothing more guaranteed to keep the public out of the picture than creating a whole new language!) but you will certainly get the gist of what's going on and opening the discussion with your doctor or neurologist may provide more information and tell you at what stage the whole investigation is at. Interesting!
Results provide hints about analgesic effects in migraine, other pain conditions
by Stephani Sutherland on 1 May 2014
Botulinum toxin type A (BoNT-A), a potentially deadly, muscle-paralyzing neurotoxin, has been famously repurposed to smooth out facial wrinkles, relax muscle spasms, and, recently, to treat headaches associated with chronic migraine. Despite intense ongoing study of BoNT-A for migraine and other pain conditions including osteoarthritis and peripheral neuropathy, researchers are still mostly mystified by the question of how the toxin stops pain. Two papers now show that BoNT-A selectively pacifies sensory neurons that detect mechanical pain in rodents and humans.
The first paper, published April 8 in Cephalagia, comes from Rami Burstein and colleagues at Harvard Medical School and Beth Israel Deaconess Hospital in Boston, Massachusetts, US, in collaboration with Allergan, Irvine, California, US (the maker of onabotulinum toxin A, marketed as BOTOX®). Burstein’s group found that BoNT-A specifically reduced neural responses to painful mechanical stimuli in both naïve and sensitized peripheral trigeminal nociceptors in rats.
“This study is the first to test BoNT-A effects on nociceptive neurons believed to mediate migraine headache,” wrote Andrew Russo in an editorial accompanying the research report (Russo, 2014). “As such, it takes us a step closer to understanding how this therapy may benefit migraine patients,” wrote Russo, a neuroscientist at the University of Iowa, Iowa City, US.
The headache component of migraine is thought to stem, at least in part, from activation of pain-sensing neurons of the trigeminovascular system, which innervate the meninges and its associated blood vessels surrounding the brain. To look at the effect of BoNT-A on those neurons, Burstein and collaborators made electrophysiological recordings from sensory neurons in the rat trigeminal ganglia while stimulating the exposed meninges with mechanical probes. Nearly half of small, unmyelinated C-fiber nociceptors became less sensitive to pain-inducing mechanical stimulation following application of BoNT-A, but the toxin did not affect cells’ responses to non-noxious mechanical stimuli.
Researchers believe that trigeminal neurons in migraine become sensitized the same way they do in other inflammatory conditions—via release of inflammatory molecules that amplify nociceptor signaling. To recapitulate that sensitization, the researchers doused the dura with a cocktail of inflammatory mediators. Spontaneous and mechanically evoked neuronal activity increased significantly following application of the cocktail; this hyperactivity was reduced back toward baseline levels after BoNT-A treatment. The toxin also worked prophylactically; pretreatment of the dura with BoNT-A prevented the increased spontaneous activity and sensitization to high-intensity stimulation in C-fibers, but again did not affect responses to non-noxious mechanical stimuli.
Together, the results indicate that BoNT-A specifically reduces high-threshold mechanical transduction in both naïve and sensitized C-fiber nociceptors. “It blocks one thing,” said Burstein, “the ability of the nerves to be activated by mechanical pain.”
That raised an anatomical question, said Burstein: “How can a drug that you inject in the scalp—outside the skull—interact with pain fibers inside the head?” Burstein’s group previously showed that trigeminal pain fibers extend nerve endings that exit the cranium through the sutures, tiny fissures between skull bones (Kosaras et al., 2009). To see whether the toxin targeted these extracranial pain fibers, the researchers applied BoNT-A outside the sutures. As with the dural application, extracranial BoNT-A did not change neurons’ spontaneous activity but assuaged their responses to strong extracranial mechanical stimuli. This suggests that BoNT-A could act, at least in part, directly on extracranial afferents.
But there may be other routes for the toxin to affect trigeminal pathways. In a recent PRF webinar, speaker Andrew Charles, University of California at Los Angeles, US, and panelists Russo, Robert Shapiro, and Gregory Dussor discussed the Burstein paper. Dussor, University of Texas at Dallas, US, said, “New studies show that BOTOX does not stay in the location where it is injected, but that it might actually move throughout the nervous system—even trans-synaptically.” So in addition to working at peripheral nerve endings found outside the skull, BoNT-A may also be transported back to the CNS and possibly to other neurons as well, he added. (See Dussor’s comment, below for further discussion.) Shapiro, University of Vermont, Burlington, US, also pointed out that BoNT-A’s enzymatic activity likely persists long after it has moved to new locales, perhaps cleaving protein targets along the way (see PRF related webinar discussion of BoNT-A starting at 1:16).
BoNT-A quiets human nociceptors, too
In a second paper, published February 18 in Annals of Neurology (Paterson et al., 2014), David Bennett at the University of Oxford, UK, and collaborators including co-first authors Kathryn Paterson at King’s College London and Stéphane Lolignier at University College London, UK, showed that BoNT-A could selectively and persistently block mechanical pain sensation in the skin of healthy human volunteers. In the study, 24 subjects received a weekly injection of BoNT-A in one leg and saline in the other. Quantitative sensory testing revealed that BoNT-A treatment blunted mechanical pain but left temperature and non-painful mechanical sensations intact. Subjects also reported less itch and pain in response to topical application of histamine and allyl isothiocynate (AITC; a pain-evoking chemical), respectively, in the BoNT-A-treated leg compared to control. Bennett’s findings indicate that BoNT-A selectively reduced mechanical pain sensitivity.
To determine if BoNT-A may target mechanical pain throughout the peripheral nervous system and in particular sensory neuron function, the group looked at the effects of the toxin on electrophysiological responses of cultured rat dorsal root ganglia neurons. BoNT-A did not change basal neuronal excitability, but fewer neurons displayed a slowly adapting, mechanically sensitive ion current in treated compared to control cultures. Other mechanically activated currents were unaffected, mirroring the team’s psychophysical findings in humans.
Both groups concluded that BoNT-A might affect an ion channel that transduces high-threshold mechanical stimuli in nociceptors. Together, Bennett told PRF in an email that the findings “provide a novel locus of action for this agent,” albeit a mysterious one. “We are still awaiting confirmation as to the molecular entity mediating noxious mechanosensation in mammals. Piezo proteins are important candidates, although the currents mediated by these channels are reported to be rapidly adapting (as opposed to the slowly adapting currents we were recording). This is a rapidly moving area, and we are eagerly awaiting the results of gene knockout studies to clarify this point,” Bennett added.
Bennett wrote, “We [and Burstein] both found that BoNT-A had a delayed effect in reducing the response to noxious mechanical stimuli.” Because of that delayed response—which took hours to develop in the rat and emerged over several weeks in the human study—the scientists concurred that BoNT-A probably does not immediately affect channel function, as some toxins do, but instead, they speculated that it may affect delivery of a mechanosensing protein or proteins to the cell membrane (for more, see comment below from Dussor).
That fits with botulinum toxin’s known mechanism of action, which is to interfere with fusion of synaptic vesicles with the plasma membrane, a key step in both neurotransmitter release and membrane protein trafficking. The idea also jibes with growing evidence for regulated subcellular translocation of TRP channels and other proteins as a driving force for nociceptor sensitization, and pain hypersensitivity.
“I think that is a real, attractive possibility,” said Russo during the PRF webinar, “and an area of cell biology that has been overlooked. There is a lot of room for botulinum toxin to act on cell mechanisms that would affect receptor localization, which would lead to plasticity and potentially cause chronic pain,” he suggested.
Many questions remain about the mechanism of action and selectivity of BoNT-A on mechanosensitive nociceptors. Paradoxically, the lethal toxin may give new life to studies on regulated protein trafficking in chronic pain and possibly offer a novel route to stopping some kinds of pain.
Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance writer in Southern California, US.
http://painresearchforum.org/news/40155-botulinum-toxin-targets-mechanosensitive-nociceptors
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