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WHETHER it is a fleeting ouch from brushing against a hot oven or a longer-lasting throb from a broken leg, pain gives us an evolutionary imperative for survival. Without it, we might allow our tissues to be singed and battered without a thought. Life-saving it may be, but pain can also be catastrophically debilitating.

And . Life expectancy is increasing, but those extra years are often associated with poorer health. Of all medical afflictions, , in particular chronic pain that lasts for more than three months (see 鈥�Viewing chronic pain as its own illness is providing better treatments 鈥�). We desperately lack effective treatments, and the ones we have bring their own problems, as evidenced by the opioid epidemic still ravaging the US, where the rate of . Pain is an increasingly challenging global health issue, hence the need for a better understanding of the experience, what causes it and how to treat it.

Remarkably, it is only relatively recently that we established a good picture of how and where the sensation of pain is created. On a basic level, this feeling is triggered in a similar way to all our sensory contact with the world around us. Receptors at the ends of sensory neurons collect information from the skin, muscles, organs, joints and any other parts of the body exposed to sensory stimuli, such as temperature, vibration and pressure. These neurons extend to clusters known as dorsal root ganglia, which shuttle signals to the spinal cord and brain.

When sensory stimuli are of a certain type and magnitude, they activate a receptor at the end of a particular type of neuron in these clusters, called a nociceptor, and the signals register as pain. This 鈥減ainful鈥� part of the process is known as nociception, the detection of noxious stimuli.

This basic mechanism for nociception has been , but the details have taken a longer time to pin down. It wasn鈥檛 until 1997, for instance, that , and his colleagues identified the gene TRPV1 and the protein it encodes, TRPV1, which is found at the ends of nociceptors and makes cells sensitive to heat both from temperature and chillies. They did this by switching on genes that aren鈥檛 usually active in cells that don鈥檛 typically respond to capsaicin 鈥� the chemical that makes chillies 鈥渉ot鈥�. They discovered a single gene that made cells sensitive to capsaicin, as well as hot temperatures. For this work, Julius shared the 2021 Nobel prize in physiology or medicine with at Scripps Research in La Jolla, California, who discovered proteins that sense touch.

Identifying TRPV1 filled in an important piece of the pain puzzle, as it offered hope of blocking the protein to treat pain. However, understanding 鈥� and ultimately blocking 鈥� the component of the pathway that shuttles the signal to the brain could provide more generic pain prevention. As it happens, this is already a rare but natural occurrence.

In 2006, at the University of Cambridge and his colleagues reported on 鈥渃ongenital insensitivity to pain鈥� (CIP), which is thought to affect just one in a million people. Those with the condition feel no pain whatsoever and, without the deterring caution it elicits, often don鈥檛 survive far into adulthood. Some of the team had travelled to Pakistan to meet a boy with CIP, who attracted attention following incidents where he reportedly pierced himself with knives and walked on hot coals as street theatre. He died tragically following a jump from a rooftop before the researchers arrived. When the team studied DNA from the boy鈥檚 extended family, including six other children with CIP, they discovered the root of the condition: a mutation in a gene called SCN9A, which provides instructions for making a sodium channel on nociceptors that makes them fire. Without it, pain signals never make it to the brain.

Is the next step a revolution in painkillers? If only it were that simple. For a start, blocking the routes used by pain signalling is prone to a plethora of hazardous and potentially fatal side effects (see 鈥�The new pain treatments that may finally stem the need for opioids鈥�). What鈥檚 more, we are increasingly understanding that nociception isn鈥檛 the full story when it comes to the mechanism of pain.

The experience of pain is nuanced, involving a 鈥溾�� 鈥� a multitude of brain areas with coordinated electrical activity. 鈥淲e know that pain is highly complex,鈥� says in California. 鈥淚t鈥檚 a noxious sensory experience, but it also includes emotional and social dimensions.鈥�

As well as nociception to tell us where it hurts, there is an affective, or emotional, system in the brain, which is even more complex and less well understood (see 鈥�Why emotions can feel so painful 鈥� and what it means for painkillers鈥�). 鈥淭he context in which we experience pain, the meaning we attribute to it, our thoughts, our emotions, the quality of our sleep the night before 鈥� all of these things can have an influence on our experience of pain,鈥� says Darnall. So, the pain we experience isn鈥檛 necessarily a reliable reflection of the threat it poses.

This link between quality of life and pain is a two-way street, and measuring things like sleep and mobility can give a window into the level of pain someone is experiencing and how to treat it (see 鈥�New ways to measure pain can help us communicate how bad it really is鈥�). In fact, attempting to wrestle with a person鈥檚 attitude to pain is one widely accepted non-pharmaceutical intervention, particularly for nociplastic pain (see 鈥�We are only just beginning to understand what causes nociplastic pain鈥�). Pain may be inevitable, but if understanding it better can diminish its impact, there is cause for hope.