Substance P, The Secret Agent on "Stress"

Stress, anxiety and depression are defined by the medical agents as the most important disorders in the 21st century. The clock has been engineered to force us live up to the minute. We basically did that to ourselves for so many social and economical reasons that are not under analysis hereby; but the constant competition we are pushed into, is surely one of them. Competition is good, though, if it drives you to appeal to the best you can, for the best you can is good enough. When you decide to use all your energies in order to reach higher than your biochemical/psychological thresholds, then clinical situations as nervous breakdowns, stress, fatigue, anxiety and depression can become common words in your daily lexicon.

We all know how hard it is to cope with the quotidian demands and stay positive on a healthy life. There are so many techniques we should definitley apply to our daily schedule in order to balance all the imbalanced energy levels within the organism, but today all I want to tell you guys is what Toxicology, as a breakthrough science, is doing for you on the background. Amongst several other branches of science, Toxicology is researching so one day we can all use the knowledge obtained to tackle this terrific disease that starts silent and forces you down to bed for quite a while, in the worth cases.

The so far undergone research drags a funny subject to the Plateau:  Substance P. It could be the nickname of a new wave actor, it could even be a post-grunge punk rock band trying its way in the musical arts, and it could also be some kind of non-toxic ink to help you safely paint your toddler´s room. But it´s not! It´s a lot more important than that; although I´m not saying your toddler is not important, actually, more and more children are to be affected, directly or indirectly, by stress and anxiety... even if it is your own when it comes to choosing Purple ocean or Tuscan oasis for the baby´s room (I totally made up these colours’ names now, don’t look for them in the IKEA catalogue)!!!

According to a review article on the role of substance P (an important element in pain perception) in stress and anxiety responses, it is said that "Substance P (SP) is one of the most abundant peptides [short polymers of aminoacids] in the central nervous system and has been implicated in a variety of physiological and pathophysiological processes including stress regulation, as well as affective and anxiety-related behaviour" [see Ebnar and Singewald, 2005]. Stressful stimuli are known to alter Substance P tissue content and its binding receptor (NK-1), i.e, in a very general way NK-1 being the one molecule that allows attachment of the substance to the tissue. Both SP and NK-1 are widely distributed in the brain tissue, mostly in areas that control and regulate emotions. 

Now, the one thing I love about Endocrinology (my second passion in science, right after Toxicology) is that everything can be perfectly and easily explained to any plebeian. So fasten your seat-belts because here we go:

Firstly, whenever emotional stressors happen to your life, SP efflux is, therefore, induced in specific parts of the limbic system (set of brain structures with very complicated names) including the hippocampus,  anterior thalamic nuclei, limbic cortex and the one thing believed to be regulating stress and anxiety - the AMYGDALA! -, a "self-circuit", the seat of emotions, the locus of feelings in the brain. 

The nucleus amigdalae are almond-shaped structures sitting in the depths of the medial temporal lobes of the brain in complex vertebrates, like us humans. The nucleus amigdalae performs primary roles in emotional events, is involved in the modulation of memory consolidation (helping the formation of the long-term memory), can be damaged by repeated episodes of heavy drinking of alcohol and withdrawal from it in a cycle, and neurophisiologically is related to Borderline Personality Disorder (characterized by deep variability mood states), Bipolar Disorder (presence of one or more episodes of abnormally elevated energy levels) and so on, and on and on.

So, how do emotions, stress, anxious feelings or anxiety-causing events can operate on the amygdala and subsequently cause secretion of substance P? And what is the impact on how we deal with life's stressful situations? Well, an initial gate to finding an answer to such a complicated question can easily be found on two ways, 1) Ask God 2) Ask Ebner et al., 2003's. The first one has been apparently busy for quite a long time, but the second one partially explains it on "Substance P in the medial amygdala: Emotional stress-sensitive release and modulation of anxiety-related behavior in rats". The referred research tested for immobilization stress and discovered "a pronounced and long-lasting increase (150%) in SP release in the medial nucleus of the amygdala (MeA), but not in the central nucleus of the amygdala"; in response to elevated platform exposure (a mild emotional stressor) SP release in the MeA was transiently enhanced (40%). These findings identified the middle nucleus of the amygdala as a critical brain area for the involvement of Substance P transmission in anxiety responses and as a supposed site of action for the recently discovered therapeutic effects of SP antagonists (agents working as the opposition) in the treatment of stress-related disorders. 

For those who are having a hard time to understand the role of Substance P, I'll now try to make it simple... Imagine nerve cells trying to communicate to one another; they do it through neurotransmitters. Substance P is a neurotransmitter and its raw function is to cause pain as a response to an infection, so you feel it and understand there is definitely something wrong with you and you go check (as in arthritis, for example). Substance P is also involved in a series of several other events like:

- defensive behaviour,

- change in cardiovascular tone,

- smooth muscle contraction,

- vasodilatation,

- stimulation of salivary secretion,

- the vomiting reflex.

Don't they look so familiar to a stress response, like for an instance, when a person is being robbed? 

1st) You would try to pull the wallet against your body;

2nd) Then your heart would start to beat fast, forcing a rush of blood through your body;

3rd) You would pull the fight-or-fly response (fight the guy or just beat the hell outta there;

4th) Your mouth would go dry;

5th) And if the robber really makes it a fearful situation, you can end up vomiting after he's gone.

Biochemically speaking, the moment your brain recognises the fearful or stressful event, anxiety triggers NK-1 receptor to "activate" this quick response from your organism. So, if it wasn't for Substance P you would probably act like a Zombie facing Shawn of the Dead!!!

Nevertheless, Substance P is also involved in other important processes for one's well being, such as:

Sex:

"Regulation by the medial amygdala of copulation and medial preoptic dopamine release" (Dominguez et al., 2001). This group of researchers showed that dopamine (a neurotransmitter present in animals) microinjected into the medial preoptic area (close to the hypothalamus) facilitate sexual behaviour with the medial amygdala inputting signals, whereas the dopamine agonists inhibit such pattern.

Social Recognition:

Oxytocin (known as the hormone of love for its role in inducing labour may influence our ability to bond with others) acts in the medial amygdala during the initial exposure, facilitating social recognition.

OK, it has been a long approach to understanding the very basics of the biochemistry of stress and anxiety. Don't forget there are many other variables that can infer and disturb your mood, and we will talk about all of them in this blog; but for the time being you know Substance P, NK-1 receptors and the Amygdala are agents to account for when approaching this issue.

What´s the triggering process again so you can tell you mum about your incredible findings? According to Ebner and Siongewald (2005): "Based on findings that SP transmission is stimulated under stressful or anxiety-provoking situations it was hypothesised that blockade of NK1 receptors may attenuate stress responses and exert anxiolytic-like effects. Preclinical and clinical studies have found evidence in favour of such an assumption". So tell your mum next time you see her that you learned this and a lot more on your

The Toxicologist Today.