The Dichotomy of Substance P in Mediating Analgesia in the PNS and Nociception in the CNS

The excitatory neuromodulator Substance P (SP) in the tachykinin family of neuropeptides is produced in the CNS and PNS. Co-release of SP and glutamate, as well as upregulation of SP’s neurokinin G Protein-coupled receptors (GPCRs) have been implicated in acute and chronic inflammation as well as nociception.¹

A number of factors secreted in response to noxious stimuli in the periphery-including proteases and growth factors-activate GPCRs and transient receptor potential (TRP) channels on peptidergic nociceptors, leading to the release of SP and other neuropeptides. Binding of SP to its neurokinin (NK1) receptors results in neurogenic inflammation and transmission of nociceptive signals centrally, through its effect on postcapillary venules and dorsal spinal neurons, respectively.¹

This latter role of SP in the spinal cord has prompted searches for NK1 receptor antagonist-based analgesics, all of which have failed.² Several studies have aimed to determine why such drugs were ineffective, a hypothesis being that this might be caused by SP exerting analgesic effects in the PNS.^3,4

In a study recently published in Antioxidants and Redox Signaling, researchers identified a novel anti-nociceptive effect of SP in sensory neurons, mediated by its inhibition of T-type, voltage-gated calcium (Ca²⁺) channels (Ca_v3s).⁵ Inhibition of Ca_v3s, which are highly expressed in dorsal root ganglion (DRG) neurons, was shown to confer analgesic properties to epipregnanolone, an endogenous steroid.⁶

Here, results indicate that binding of SP to NK1 receptors on small diameter DRG neurons leads to Ca_v3s inhibition through generation of reactive oxygen species (ROS). This redox is mediated by SP through enhancement of Ca_v3s sensitivity to extracellular zinc. In addition, researchers showed that in vivo Ca_v3s knock-down in DRG neurons decreases anti-nociceptive effects of SP in response to an induced painful stimulus.

The present study uncovered 2 cumulative mechanisms whereby SP exerts its anti-nociceptive effects peripherally: through concurrent inhibition of excitatory T-type Ca²⁺ channels, and ROS-mediated activation of inhibitory M-type potassium channels. Authors have thus described a novel SP-mediated mechanism for endogenous analgesia.

“If we could develop a drug to mimic the mechanism that Substance P uses, and ensured it couldn’t pass the blood brain barrier into the CNS, so was only active within the peripheral nervous system, it’s likely it could suppress pain with limited side effects.” said the study lead author, Dr Gamper in a statement.

References

1. Steinhoff MS, Von mentzer B, Geppetti P, Pothoulakis C, Bunnett NW. Tachykinins and their receptors: contributions to physiological control and the mechanisms of disease. Physiol Rev. 2014;94(1):265-301.
2. Substance P (NK₁) Receptor Antagonists—Analgesics or Not? The handbook of experimental pharmacology. Chapter Tachykinins Volume 164 of the series Handbook of Experimental Pharmacology pp 441-457. Available at: http://link.springer.com/chapter/10.1007%2F978-3-642-18891-6_13. Accessed on August 1, 2016.
3. Thornton E, Vink R. Substance P and its tachykinin NK1 receptor: a novel neuroprotective target for Parkinson’s disease. Neural Regen Res. 2015;10(9):1403-5.
4. Urban LA, Fox AJ. NK1 receptor antagonists–are they really without effect in the pain clinic? Trends Pharmacol Sci. 2000;21(12):462-4.
5. Huang D, Huang S, Gao H, et al. Redox-Dependent Modulation of T-Type Ca(2+) Channels in Sensory Neurons Contributes to Acute Anti-Nociceptive Effect of Substance P. Antioxid Redox Signal. 2016;25(5):233-251.
6. Ayoola C, Hwang SM, Hong SJ, et al. Inhibition of CaV3.2 T-type calcium channels in peripheral sensory neurons contributes to analgesic properties of epipregnanolone. Psychopharmacology (Berl). 2014;231(17):3503-15.