In a previous post Curious cat asked what pain was. The question is simple, but the answer certainly is not. I vaguely recalled sitting through some pharmacology lectures on pain, so thought I could make a post out of it.
Except, when I started looking up what pain was I found out that the whole phenomenon of pain is far, far more complex than what I can bottle down in a single article. However, I think my reductionist and simplistic knowledge of pain might suffice in providing a broad, very general outline of pain, so here goes.
Our sensory system is complex, and pain is amongst our most complex senses. The sensory systems (smell, taste, feeling (and pain), sight) all evolved primarily to help the organism survive better, by locating food better or sensing enemies or predators better and so on. Pain is one of the most obvious warning systems the body has. When something hurts, your body immediately responds by trying to get away from the pain.
Pain is also differentiated into acute and chronic pain. Acute pain is sudden, and is limited to a short time. For example, a stubbed toe hurts, but the pain subsides as soon. Chronic pain though can last a long time, and is indicative of a more serious ailment which may not be obvious, but could be extremely damaging.
But how is pain actually perceived at a molecular level? There are numerous nerve fibers throughout the body that sense pain, and these nerve fibers transmit information to the spinal chord, which in turn relays the information to the brain. These nerve cell receptors, which are unspecialized nerve endings that actually initiate the sensing of pain, are called “nociceptors”. The nociceptors themselves form two or three major classes (depending on how you classify them). There are mechanosensitive nociceptors (which sense pressure), mechanothermal nociceptors (temperature and pressure) and polynodal nociceptors. The nociceptors themselves are made up of A-fiber nociceptors, which mediate that fast, prickly sensation of pain, or C-fiber nociceptors, which conduct pain more slowly, and are responsible for the throbbing or burning sensation of pain. Now, many sensory nerve endings respond to nonpainful mechanical or thermal stimuli, but nociceptors are designed only to respond to high levels of mechanical or thermal stress, which subsequently cause pain. The threshold of activation of these nociceptors is very high, and they don’t respond when say you are exposed to lukewarm water, or to cool temperatures (like in the post describing the receptor for cool temperatures).
At a more molecular level, these different types of nociceptors all express different classes of ion channels, which provide the molecular specificity for sensing different pain. To give a molecular idea of how pain is perceived through these different channels, I’ll use a very recent example from a paper in Nature. Here, researchers describe the role of a very specific channel called Nav1.8. This is a “voltage gated sodium channel” that excites the nociceptors under extreme cold. Ion channels are proteins that form pores across cell membranes, and then specifically allow certain ions across. By doing so, they can maintain an electrochemical or voltage gradient across either side of the membrane. By opening and closing, the ion channels allow specific ions across, and thus change the electrochemical gradient. This results in an electrical impulse. In a nerve cell (including these nociceptor cells), when this happens, the cell releases molecules called neurotransmitters at the end point of the nerve, called a synapse. These neurotransmitter molecules can then go across to the next nerve cell at the synapse, and then pass on the information to the next nerve cell, and finally the information reaches the brain and is processed.
So, coming back to Nav1.8, this is a channel specific for Sodium ions, and only allows sodium ions across. Now, different stimuli open different ion channels, and this particular channel, found in nociceptors, responds to extreme cold. When exposed to extreme cold (which will cause pain), these channels remain open, and pass this information on to the brain. When the researchers started work on this ion channel, it was not known what role it played in extreme cold perception. So, what they did was to knock-out this protein in mice (just like the other experiments in the previous post on cold). Normal mice, when kept on a cold plate (at zero degrees Centigrade) will hop about, lift their feet, and be extremely uncomfortable. But in the mice where this Nav1.8 protein was removed, they would be impervious to cold, and calmly stand and freeze.
Similarly, for different stimuli (which can cause pain), there remain different proteins that sense them, and relay the information to the brain, usually saying “ouch” in different ways. Because pain works through these specific receptors and neurotransmitters, drugs can be designed to block them (opiods, including opium and morphine, work by blocking these neurotransmitters), and so we can “treat” pain.
But pain is also perhaps the most subjective of all senses. The threshold for pain varies dramatically for different people. Some people can tolerate extreme pain, others can’t. This mental component of pain is far more complex (I hardly understand it fully, so cannot explain it well in this article), and a lot of pain is indeed purely from the mind. But given how important pain is to all of us, I think we’ll always remain interested in knowing how it happens.
Thanks Sunil, that gives me the toe hold I was looking for...now, a question. You said that the pain killers that are opiates block the neurotransmitters. But, how do generic things like acetyl salicilic acid or acetamenophen work? By blocking the ion channel in the nociceptor? I mean, they should not affect the neurotransmitters right?
Curious cat....all good questions, but the answers are not very simple, since pain is a complex phenomena.
Morphine and other opiod agonists work by acting on opoid receptors, and activating a bunch of downstream pathways that finally end up reducing neurotransmission from nociceptors.
However, asprin and other salicylates (which are all non-steroidal anti-inflammatory drugs or NSAIDs) work completely differently. They inhibit a group of enzymes called cyclooxygenases (Cox). These enzymes help make prostraglanding, which is critical in inflammation. So, by inhibiting these enzymes, asprin and other drugs help reduce inflammation substantially, and since inflammation triggers pain, lowering inflammation reduces pain.
Acetaminophen though is an interesting case, and the mechanism of action is still not fully clear. It was thought to inhibit these Cox enzymes, but does so only very weakly, and does not have too many anti-inflammatory effects. However, recent studies suggest that it might specifically inhibit a new Cox enzyme (Cox3), and the effects seen might be through that. The jury is still out for that. But acetaminophen is undoubtedly less effective than strong NSAIDs.
It's sort of interesting to think about the difference between acetaminophen and aspirin or other salicylates. If you assume that both of these acetylate serines in Cox, then you would intuitively think that aspirin would do the job better because since it's an ester, it has better leaving group ability than the amide in acetaminophen, and therefore would be more reactive. I wonder if that effect contributes to the relatively weak action of acetaminophen on Cox.
ashutosh....that's an interesting point, and may well be true. At least in vitro, acetaminophen only weakly inhibits the Cox enzymes.....so some people think acetaminophen doesn't really work through Cox at all. It'll be interesting when it is all figured out.
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