This is a very technical article about a very odd, and thus interesting, phenomenon.
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.
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.
This latter role of SP in the spinal cord has prompted searches for NK1 receptor antagonist-based analgesics, all of which have failed. 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
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.
Those are awfully many “if’s”
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- 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.
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