_{Salix alba (License: CCO-BY-SA 2.5 unported]:
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#### INTRODUCTION
It all started from the discovery of the willow tree. Salix alba was discovered to have medicinal properties that could relief of pain, fever and even headache. The major useful component was called Salicylates. This is the major components in our common pain relieve and fever drugs. A second plant was also discovered, the Spiraea ulmaria. The combination of the plants gave the aspirin[a for acetyl spi for spirsaurea the acid gotten form the Spiraea ulmaria.] Conventionally Aspirin became the most used for of pain relief.
#### PAIN IS A DREAM.
That term I got from a movie once watched. They trained soliders to become spies to carry out undervover work and during the training as they made them endure certain torture the commander kept saying "Pain is a dream". The idea was to condition their minds so they wouldn't cave under the pressure of pain. But what exactly is pain ? Sensation, feeling, it may be created by various means: hot, cold, pressure... but it all boils down to a series of bio-signaling reactions that occur in less than a millisecond hence giving an immediate reaction to whatever has caused us pain. Try using a sharp object to prick your finger or any part of your body, the normal response would be to pull away from the sharp object and probably yell a little. But the pulling away is simple reflex that occurs within the spinal cord that makes you react by pulling away even before you feel pain. What actually happens here is simple. The point of contact with the sharp object experiences tissue damage which is registered by microscopic pain receptors in the skin. Inflammatory mediators are produced and this leads to the activation of prostaglandins EP and cytokinne receptors. Each pain receptor is connected to a neurone at one end and the other end is connected to the spinal cord by a nerve fiber. Activation of pain receptors sends electrical signals up the nerve fiber and straight to the spinal cord before it reaches the brain across synapses by means of chemical messengers.
The brain however may interprets pain sometimes based on the context or the situations surrounding the cause of pain. Just like I explained earlier, a solider being trained to think of pain as a dream would most likely display much less pain than a civilian that is wounded. The relay of the the chemical signals from the synapses to the brain(thalamus) is more or less the same as transferring a whole box of papers to a room for sorting. The thalamus is like the sorting center. The sensory impulses sent from the receptors to the thalamus may either be transmitted as a fast pain message directly to the cortex of the brain where a higher level of thinking takes place. Pain from a prick on the finger would be followed by an immediate reaction of pulling away due to this reason. However, the transmission of a slow pain message would go to the hypothalamus of the brain which is associated with the release of certain hormones e.g stress hormone and to the limbic system associated with emotions. This is why cases of chronic back pain is usually associated with stress and depression.
#### In attempt to relief pain the main target was the prostaglandins.

_{COX-2 inhibitor Flurbiprofen (License: CCO 1.0-Public Domain]:
Wikipedia Commons}

A lot of physiological activities involve prostaglandins. Pain being one of the very few of them. In mammals prostaglandins have two isozymes which have different functions but the same amino acid sequence and similar reactions at their catalytic center. Aspirin and other NSAIDS(nonsteriodal antiinflammatory drugs) are used to relief pain by blocking the synthesis of these prostaglandins associated with pain. The two prostaglandins isozymes are the COX-1 associated with the secretion of gastric mucin and the COX-2 associated with inflammatory response to pain and fever(cycloxygenase 1 and 2 respectively). Aspirin and other NSAIDS acts as an inhibitor of cyclooxygenase that mediates the conversion of arachidonic acid to inflammatory prostaglandins. Let's simplify it further. This inhibition is somewhat similar to the zip of a dress. If a loose thread gets in its way it becomes stuck in place and unable to move until you figure out a way to remove the obstacle. Same goes for cyclooxygenases and Aspirin or any other NSAIDS. They help reduce pain by attaching to the active site of the COX-1 and COX-2 enzymes preventing them from making prostaglandins and thereby lowering the level of pain traveling to your brain.
#### The Search Continues For a Better Relief.
The therapeutic effect is in the active sites of the isozymes, especially in that of the COX-2 associated with inflamtory response to pain and fever. The atta hment to the COX-1 active site is the reason for the side effects like gatrointestinal and renal toxicity since the COX-1 is functional in gastric mucin secretion than in pain response. Scientists have taken time to study the three dimensional structures of the two isozymes COX-1 and COX-2 and have discovered their identical tertiary and quartenary structures although differing in long and thin hydrophobic channels extending to the membrane interior of the lumeneal surface. Crystallizing COX-1 and COX-2 in the presence of several NSAIDS compounds have shown that the drugs the hydrophobic channel and the entry of arachidonate whcih is a very important precursor of prostaglandins. The difference in the structures of the COX-1 and COX-2 is the sole guide in developing NSAIDS that would potently inhibit COX-2 more effectively than COX-1.
The active sites of the COX 1 and 2 differ in sequence by the single amino acid difference at the active site(valine 509 to isoleucine).This difference was the basis of the selectivity of the newly developed NSAIDS compounds to COX-2 . This means that a single amino acid substitution of isoleucine at position 509 to valine was sufficient enough to develop new inhibiting compounds that would favour COX-2 inhibition. Drugs like Celecoxib used for treating osteoarthritis and rheumatoid arthritis have been proven clinically to inhibit the COX-2 more effectively although they have shown potent side effects affecting the heart. Refecoxib used in treating muscluoskeletal pain and osteoarthritis also inhibit COX-2 activity lowering the volume of pain an giving less side effects associated with renal and stomach irritation.
#### Final Thoughts
The effectiveness of the COX-2 inhibitors in pain relief although clinically proven still shows some side effects causing hypertension, stroke and in extreme cases acute myocardial infarction. Some have been taken of the market because of the overall risk factor being high. Valdecoxib and Rofecoxib being of the the FDA disapproved NSAIDS. It is advisable to not self prescribe NSAIDS to avoid long term use and wrong dosage intake which may be fatal to the health of the consumer. ------- _{I am a proud member of the Steemstem community that rewards quality posts in the science, engineering, mathematics field. Feel freee to join our discord group by following this [link]()} ------- #### References ------- _{1. Charlier C, Michaux C. Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) as a new strategy to provide safer non-steroidal anti-inflammatory drugs. Eur. J. Med. Chem. 2003;38:645–659. [PubMed]} _{2. Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu. Rev. Pharmacol. Toxicol. 1998;38:97–120. [PubMed]} _{3. Merck Manual Home Health Handbook. Overview of pain (updated Aug 2007). http://www.merckmanuals.com/home/brain_spinal_cord_and_nerve_disorders/pain/overview_of_pain.html (accessed Mar 2012).} _{4. Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell. 139(2):267-84. Pan HL, Wu ZZ, Zhou HY, Chen SR, Zhang HM, Li DP (2008) Modulation of pain transmission by G-protein-coupled receptors. Pharmacol Ther. 117(1):141-61. Petho G, Reeh PW (2012) Sensory and signaling mechanisms of bradykinin, eicosanoids, platelet-activating factor, and nitric oxide in peripheral nociceptors. Physiol Rev. 92(4):1699-775. Schaible HG (2007) Peripheral and central mechanisms of pain generation. Handb Exp Pharmacol. 177:3-28. Schaible HG, Ebersberger A, Natura G (2011) Update on peripheral mechanisms of pain: beyond prostaglandins and cytokines. Arthritis Res Ther. 13(2):210. Scholz J, Woolf CJ. (2002) Can we conquer pain? Nat Neurosci. 5 Suppl:1062-7. Woolf CJ, Ma Q (2007) Nociceptors--noxious stimulus detectors. Neuron. 5:353-64.} _{5. http://www.mydr.com.au/pain/pain-and-how-you-sense-it} _{6. http://www.mydr.com.au/pain/pain-and-how-you-sense-it}