Substance P: Nerve Pain Killer Or Pain Promoter?

Today's post from the ever-reliable sciencedaily.com (see link below) is an interesting one because it explains in terms we can all understand, a peculiar paradox that occurs in both the central and peripheral nervous systems concerning a mysterious substance called 'Substance P'. Now apparently, if substance P is found in the central nervous system (brain and spinal cord) it excites pain cells and causes more pain but if it is found in the peripheral nervous system (the rest of the body) it acts as a natural pain killer and prevents pain cells from becoming over-stimulated. So, what does all this mean? It means that drugs used to suppress substance P have actually caused more pain, when targeted at the peripheral nerve system and that has led to new drug 'failures' when in fact, they should have been used to suppress substance P in the central nervous system. Scientists are excited by this discovery because drugs that will promote substance P in the peripheral system will act as genuine pain killers. It's a question of targeting the right places. The article explains it much better but it's worth a read to see how research is progressing on our behalf.

'Pain paradox' discovery provides route to new pain control drugs
Date:July 28, 2016 Source:University of Leeds

A natural substance known to activate pain in the central nervous system has been found to have the opposite effect in other parts of the body, potentially paving the way to new methods of pain control.

The discovery could explain the repeated -- and costly -- failure over the last 20 years of clinical trials of potential pain-killing drugs that targeted the substance, known as 'Substance P'.

Substance P is produced in both the central nervous system (CNS) -- the brain and spinal cord -- and in our peripheral nervous system (PNS) -- all the other nerves and nerve cells that send signals to the brain.

The new research, by the Hebei Medical University in China and the University of Leeds in the UK, has found that, in the peripheral nervous system, Substance P makes nerve cells less responsive and excitable, thereby reducing sensations of pain. This is in direct contrast to its role in the central nervous system, where it triggers very different signals, exciting neurons and so promoting pain.

Lead researcher Professor Nikita Gamper, from the University of Leeds, explains: "We were really surprised by the results -- Substance P is described in the literature as a molecule that gets nerve cells excited and promotes pain. But we've discovered a paradox -- that in the peripheral nervous system it acts as one of the body's natural painkillers and actually suppresses pain.

"This means that when drugs were used in trials to suppress Substance P's action in the central nervous system, they may have also prevented it from acting as a painkiller in the peripheral system. So, although the drugs looked like they worked in the lab, when they moved to clinical trials, they failed."

Substance P works in the peripheral system by modulating the action of certain proteins that control the ability of pain-sensing neurons to respond to 'painful' stimuli. In particular, Substance P makes one type of these proteins extremely sensitive to zinc, so that natural trace levels of zinc in circulation are enough to dampen their activity and suppress the neuronal responses.

Professor Gamper -- who is also a visiting professor at Hebei Medical University -- believes this discovery could open the door to new drugs that don't have the negative side effects currently associated with stronger painkillers.

"Drugs like morphine hijack the body's natural painkilling mechanisms, such as those used by endorphins, but because they act within the central nervous system, they can affect other brain cells that use similar pathways, leading to side effects such as addiction or sleepiness," says Professor Gamper. "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."

The study -- which looked at the action of Substance P within nerve cells in the lab and in animal models -- focused on acute pain, but Professor Gamper aims to look at its role within chronic pain as well.

Story Source:

The above post is reprinted from materials provided by University of Leeds. Note: Materials may be edited for content and length.

Journal Reference:
Dongyang Huang, Sha Huang, Haixia Gao, Yani Liu, Jinlong Qi, Pingping Chen, Caixue Wang, Jason L. Scragg, Alexander Vakurov, Chris Peers, Xiaona Du, Hailin Zhang, Nikita Gamper. Redox-Dependent Modulation of T-Type Ca2 Channels in Sensory Neurons Contributes to Acute Anti-Nociceptive Effect of Substance P. Antioxidants & Redox Signaling, 2016; 25 (5): 233 DOI: 10.1089/ars.2015.6560

https://www.sciencedaily.com/releases/2016/07/160728105608.htm