Why do plants produce painkillers?

Plants do not feel pain. They do not have a nervous system and even more important they do not have a brain to integrate external stimuli. Then, why do they synthesize painkillers? Ok, maybe we need to make a step back. Aspirin, morphine, codeine, and cannabinoids are all drugs with a significant analgesic effect, and all share another feature: they are plant derived chemicals.
Aspirin is the trade name of acetylsalicylic acid. This compound was obtained by modification of a plant chemical extracted from the willow bark, salicin, which by itself already shows analgesic activity. Salicin and other structural analogues are collectively known as salicinoids and are found in members of the Salicaceae family, like willow and poplar. Salicylic acid, which is even more structurally similar to aspirin, is instead widespread in the plant kingdom.

How did man come to isolate a painkiller from the willow bark?

Plants containing salicin have been used as analgesics for a long time and across many ancient cultures from Europe, Asia, and America. Neanderthals fossils containing remains of poplar bark in their dental plaque were found, suggesting that individuals chewed the plant to relieve the pain of dental abscesses (1). Egyptians used the willow leaves to prevent fever and pain, and ancient Greeks also were very aware of its properties. Indeed, Hippocrates (4^th century BC) gave willow leaves to women to chew as a pain reliever during childbirth (2). Surely independently, also the American Indians discovered the properties of willow bark; long before Columbus they used its mashed extracts as compresses to relieve pain (3).
Despite the awareness of the effects of these treatments, the active principle remained unknown for long. However, in 1828, the German scientist Buchner isolated a small amount of salicin from willow bark (2). Around ten years later, an Italian chemist, Piria, separated salicin into a sugar and an aromatic compound that could be converted into an acid (2). This acid was named salicylic acid, after the Latin name of the white willow (Salix alba). In 1859, Hermann Kolbe and co-workers synthesized salicylic acid, leading to a boost in its use because of increased availability and reduced costs (1). Nonetheless, this drug was not exactly palatable and had several side effects, including stomach irritation and bleeding.
Side effects that were overcome by the introduction of a new derivative, acetylsalicylic acid, over whose synthesis there has been a long paternity dispute. The synthesis in a chemically pure and stable form is now attributed to Felix Hoffmann (the same chemist who obtained heroin from morphine) (1). Acetylsalicylic acid was then commercialized by Bayer, under the trade name Aspirin, rapidly becoming one of the world’s best-selling drugs.

So, why do we find this painkiller in plants?

As often happens, our anthropocentric view of the world, led us to explore what causes the willow bark or the poplar leaves to work as painkillers, but it was not until (relatively) recently that somebody asked what is the function of the compounds in the plant.

Salicin and salicinoids
Salicin is very abundant especially in some species of the Salicaceae family. It is the glucosilated form of salicylic alcohol (which in turn is the reduced form of salicylic acid). This compound seems to be used by plants as a defence mechanism against herbivores (4). Nonetheless, now we need to add a new level of complexity in the framework of the use of plant metabolites. If you had the chance to read about caffeine, you already know that plants use these compounds, which we like to call specialized (or secondary) metabolites, to defend themselves from threatens to their survival. Furthermore, we know that humankind exploits these chemicals for its own benefit. Well, turns out that we are not the only ones: some insects take the metabolites from plants and store them to use as a chemical weapon for their own defence. For example, the red poplar leaf beetle (Chrysomela populi) larvae take up the salicin from the poplar leaves they feed on and store it in defensive glands, located on the surface of their body (5). The larva uses this salicin to synthetize another chemical, salicylaldehyde, which is emitted as a deterrent against predators, like ants. Chrysomela populi is not the only case of a species that sequesters salicin. Females of some other species incorporate salicin into their eggs and transform it to salicylaldehyde before hatching, as a way to protect the larvae (4).
However, going back to plant defence, poplar and willow trees also produce many other derivatives of these compounds, known as salicinoids, with a plethora of functions (4).

Salicylic acid
Differently from salicinoids, salicylic acid (2-hydroxybenzoic acid) is widespread in the plant Kingdom (and in prokaryotes as well). However, it is usually present in low amount, except (to our knowledge) in Filipendula ulmaria, a member of the rose family, which accumulates large amounts of this compound (2).

Salicylic acid is considered a phytohormone, which means that it is a mobile signal that regulates a series of important processes, by acting at low concentrations. In particular, it is a defence-related hormone, leading to the activation and regulation of multiple responses to biotic and abiotic stresses (6). Remarkable is its role in plant immunity.
Unfortunately, besides herbivores, plants can also be attacked by fungal, bacterial, or viral pathogens. However, they are able to respond to these infections by activating an immune-like response. At first, they restrict the spread of pathogens to a small area around the point of initial penetration, through the so-called hypersensitive response, in which the cells around the area, undergo a protective cell suicide (3). The death of these cells, right around the pathogen penetration site, avoids its further spread. Salicylic acid is initially accumulated at the local infected tissue and it was thought to be then distributed all over the plant to induce systemic acquired resistance (SAR) at non-infected parts away from the infection site (3, 6). In such a way also other tissues of the plant are better protected towards further infections. It was recently shown that salicylic acid is not the mobile signal for SAR, nonetheless it is surely required for the establishment of resistance in distal parts of the plant as well, where a significant increase is anyway observed (6), probably due to biosynthesis in loco.
Even in absence of pathogens, salicylic acid can induce this immune response. Also its methyl ester (volatile) was thought to be involved in the induction of SAR, but this is still under debate (6).

It is now clear that salicylic acid is involved in many other processes, like resistance and tolerance to many abiotic stresses, including ozone, UV radiation, heat, cold, metal, and salinity/osmotic stresses. In addition, there is evidence that application of this compound affects multiple aspects of plant growth and development, including seed germination, vegetative growth, flowering, fruit yield, senescence, stomatal closure, thermogenesis, photosynthesis, respiration, and other metabolic processes (7).
Since it is a potent tool for sustainably mitigating environmental stresses in many plants, its possible application in agriculture has been proposed, but this needs further studies.

More plant derived painkillers

There are other painkillers synthesized by plants, all less safe than aspirin, and these include the opiates morfine, codeine and several semi-synthetic derivatives. Morphine derives from the opium poppy flowers (Papaver somniferum) and is a strong analgesic and narcotic. It is still largely used in pain therapy, but only in extreme cases, like in pain relief in terminally ill patients, because it is a psychoactive drug, with several adverse side effects and causes dependence. Codeine is an analogue of morphine, very similar to the previous one and has been extensively used. It was very popular not only as painkiller, but also as antitussive and that is why it was used in cough syrups. Its use is still accepted in specific formulations, but special care should be taken since it was shown that it is chemically modified in the liver to give morphine (and other compounds).
Other natural products with analgesic properties are the very popular cannabinoids, from Cannabis sativa.
However, the role in the plants is still not clear neither for opiates, nor for cannabinoids and there will be the chance to better explore these topics in the future.