Resiniferatoxin: the hottest chemical you’re not using

Deleting neurons and treating pain like a molecular scalpel, resiniferatoxin is something you should definitely be looking at.

Resiniferatoxin (RTX), coming from the cactus-like plant, Euphorbia resinifera, is powerful stuff. It’s so powerful in fact that rather than just being mildly annoying like its 1,000-times less-potent analog, capsaicin, RTX holds vanilloid receptor subtype 1 (VR-1 or TRPV1) ion channels wide open to allow sodium and calcium to flood in. The intracellular calcium toxicity that ensues is so severe that it destroys the nerve terminals if the exposure is long enough.

Take a quick look at our testing data in cells. You can see just how well RTX induces a calcium influx via TRPV1 activation at concentrations as low as the nanomolar range:

But RTX doesn’t affect just any neurons. Oh no. RTX is very selective as it only affects those neurons expressing the TRPV1 ion channel. And it just so happens that the fibers you predominantly find TRPV1 on are those that transmit pain.

A molecular scalpel

Suddenly, you have a very potent chemical with a high affinity for afferent sensory pain neurons that leaves other sensory neurons unaffected. That should pique your interest as RTX has real potential in the realms of relieving pain in a specific area.

By injecting RTX at a discrete location, it physically deletes TRPV1-expressing Aδ and C-fiber cells¹ in the dorsal root ganglia (DRG). When you eliminate the sensory neurons you effectively stop pain transmission along the spinal cord and up to the brain before it begins. Ronald Wiley and Douglas Lappi called the super-selective ablation of specific neurons “molecular neurosurgery” and said that RTX was like a “molecular scalpel.”²

Already, trials are underway to put RTX to the test to determine its efficacy in treating localized pain in diseases like knee osteoarthritis.³

Fixing knee pain

The pain-relieving benefit of RTX has already been explored in canine research where the pain relief lasted for months to even years⁴ – way more than the 2–3 weeks predicted. The authors think that in addition to shutting off nociceptive neural activity, RTX may have disease-modifying actions. How? By affecting inflammation states. Since neurogenic inflammation at least partly maintains levels of chronic inflammation RTX may have a role in lessening this, with subsequent reductions in plasma extravasation and edema.

Interestingly, while we’re talking about inflammation, a team from Germany, using RTX and a TRPV1 antibody from us, looked at the effects of intrathecal RTX on TNF in rats. Their research showed how RTX reduces tumor necrosis factor (TNF)-induced pain.⁵ As a proinflammatory cytokine, TNF plays a role in both the initial development and maintenance of neuropathic pain, and the receptors for which are in DRG neurons, and nerve injury upregulates these. The far-reaching effects of RTX continue to be impressive – not to mention raising lots of new questions to pursue!

Relief for cancer patients

But treating knees may seem quite niche, so what about broader pain issues? Patients with bone cancer, for example, sometimes have to deal with tremendous amounts of pain during their end-of-life care. This can place a heavy emphasis on opioid use, which, of course, comes with its own issues. Instead, RTX may offer some relief on a whole new level.

Rather than injecting into a small site, like the knee, in advanced cancer patients, RTX is injected into the cerebrospinal fluid around the spinal cord. Work by people like Andrew Mannes and John Heiss, for example, have been doing just that. A Phase I trial back in 2014⁶ gave 10 patients with 3–26 mg of RTX intrathecally while under sedation (to protect them from the pain of RTX itself).

Early results were mixed, but they did confirm that RTX selectively and irreversibly ablates neurons that transmit pain. An NIH trial continues to investigate RTX as a powerful treatment for pain associated with advanced cancer.⁷

RTX up- and down-regulates pain genes

It’s important to remember just how potent RTX is when it comes to pain relief. Transcriptomic work comparing RTX with capsaicin revealed that while RTX upregulates more non-pain-related genes,⁸ it also downregulates more of the off-target (i.e., undesired) pain genes. So, we see that RTX was better than capsaicin at downregulating multiple desired pain-associated genes like Camk2a, Scn11a, Adcy5, Cacna2d1, Ntrk1, Runx1, and Scn10a, it also downregulated undesired pain-associated genes like Kcnk2, Kcnj5, Gal, Nt5e, Gfra2, and Ptgdr.

So, while RTX is undoubtedly more potent than capsaicin, there is the potential for RTX to have unknown side effects.

Do more with less

As an ultrapotent analog of capsaicin RTX is almost 1,000 times more potent, as we’ve mentioned, and has few acute excitatory effects. Compared with capsaicin, RTX tends to cause desensitization⁹ while capsaicin induces excitation.

In bladder and urinary work, for example, intrathecal RTX at 100 nmol/l can cause full desensitization,¹⁰ but capsaicin needed to be administered at 1 mmol/l to get the same result. And at these low concentrations, RTX caused little irritation to bladder afferent neurons.

This means you could use RTX alongside capsaicin in your pain research and elicit similar responses at a significantly lower dose.

If you’re interested in research into RTX, TRPV1, or just pain in general, you might want to take a look at some of the in-house-made reagents we have to offer. From RTX itself, to TRPV1 antibodies and small molecules, we’re sure there’s something you’ll find interesting

Find your RTX and TRPV1 reagents now

References

1. Karai, L. et al. Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control. J. Clin. Invest. 113, 1344–1352 (2004).
2. Wiley, R. G. & Lappi, D. A. Targeted toxins. Curr. Protoc. Neurosci. Chapter 1, 1–11 (2001).
3. NCT03542838. Study of Resiniferatoxin for Knee Pain in Moderate to Severe Osteoarthritis. https://clinicaltrials.gov/ct2/show/record/NCT03542838.
4. Iadarola, M. J., Sapio, M. R., Raithel, S. J., Mannes, A. J. & Brown, D. C. Long-term pain relief in canine osteoarthritis by a single intra-articular injection of resiniferatoxin, a potent TRPV1 agonist. Pain 159, 2105–2114 (2018).
5. Leo, M. et al. Intrathecal Resiniferatoxin Modulates TRPV1 in DRG Neurons and Reduces TNF-Induced Pain-Related Behavior. Mediators Inflamm. 2017, (2017).
6. Heiss, J. et al. (364) A Phase I study of the intrathecal administration of resiniferatoxin for treating severe refractory pain associated with advanced cancer. J. Pain 15, (2014).
7. NCT00804154. Resiniferatoxin to Treat Severe Pain Associated With Advanced Cancer. https://clinicaltrials.gov/ct2/show/record/NCT00804154.
8. Singla, R. K., Sultana, A., Alam, M. S. & Shen, B. Regulation of Pain Genes—Capsaicin vs Resiniferatoxin: Reassessment of Transcriptomic Data. Front. Pharmacol. 11, 1–15 (2020).
9. Szallasi, A. & Blumberg, P. M. Vanilloid receptors: New insights enhance potential as a therapeutic target. Pain vol. 68 (1996).
10. Rackley, R. R. & Shenot, P. J. Chapter 21 – PHARMACOLOGIC NEUROMODULATION. in Female Urology (Third Edition) (eds. Raz, S. & Rodríguez, L. V) 257–265 (W.B. Saunders, 2008). doi: https://doi.org/10.1016/B978-1-4160-2339-5.50070-7.