We humans hurt constantly, the older we get, the more we become aware of it. Few things in life are as unpleasant as experiencing pain, which begs some foundational scientific question:
How is pain created, and why does our body make us suffer?
This simple-looking question is not without its depth, despite our intuition. Pain sensation is a complex phenomenon, as it involves the somatosensory system, the spinal cord and the brain, and can originate anywhere along this axis.
The “acute” feeling of pain that we are most familiar with is our brain’s interpretation of electrochemical signals that shoot through our nerve fibers after stimulation of nociceptive neurons in our skin, muscle, joints or internal organs. Nocireceptors are sensors of extreme temperatures, intense force, acid or noxious chemicals. Basically markers for injury or dysfunction of our body. Acute pain produced in our brain serves as a crucial alarm signal which aims to protect us from injury and behave accordingly to minimize it. Humans not feeling pain (a rare condition called CIP) usually don’t survive into adulthood because of unnoticed illnesses or injuries.
In some sense, this is old news. Nociceptive neurons that convey pain signals were first described in 1906 by Charles Scott Sherrington, which brought him the Nobel Prize in Physiology/Medicine a quarter century later. However, while nociception and acute pain sensing as evolved adaptive response to prevent damage is well established (Nesse RM & Schulkin J., Phil. Trans. R. Soc., 2019), it is unfortunately only part of the story of our suffering.
Between 10.4% and 14.3% of the population of the UK report severely disabling chronic pain that is either moderately or severely limiting
Pain is complicated, and this starts already at it’s evolutionary history, its biological mechanisms, it’s cognitive imprint and of course its impact on behavior (Walters ET. et al., Phil. Trans. R. Soc., 2019). In that sense, pain is very much an “interface” phenomenon between the biological reality of our bodies, and the virtual reality created by our brain. On top of that, pain complexity is hard to study in humans because of ethical considerations.
[…] The enormous complexity of pain-linked behaviour (including uniquely complex social behaviour in humans) and of pain’s intricate substrates involving large parts of the human nervous system, plus the ethical impermissibility of controlled studies on severe and/or chronic pain induced experimentally in healthy human volunteers […]— Walters ET. et al., Phil. Trans. R. Soc., 2019
This problem becomes especially salient when talking about chronic pain. Chronic pain is a big burden on societies, which can impact the lives of about one-third to half of the adult population, increasing with age or comorbidity, and with varying degree of functional limitations (Fayaz A. et al., BMJ, 2015).
The neuronal roots of chronic pain
While nociceptive stimuli are detected by sensory neurons, signal transmission runs via intermittent neurons of the spinal cord before being processed by brain.
Damaging these intermittent neurons or the neural circuitry within the dorsal horn of the spinal cord can lead to persistent and chronic pain. Please note that there is also always a psychological aspect to pain in addition to physiological factors, and dissociation of these factors is not straight forward (Roy M. et al., Eur J Pain, 2011).
At a cellular level, chronic pain arises when neurons in the pain signaling pathway lose their ability to properly regulate their excitability, often without any participation of nociception or acute pain stimulus.
Researchers have identified many molecular candidates that are proposed to be involved in these pathological pain processes (Bourinet E. et al., Physiol Rev., 2014). However, identifying functional roles of individual molecular players in physiological pain processing, or molecular functions disrupted by pathological conditions, that cause runaway hyper-excitability and subsequent chronic pain are still an active field of investigation (Kocot-Kępska M. et al., MDPI, 2021).
One limitation is that dissecting the molecular mechanism of neuropathic pain have been technically challenging for scientists, but recent advances in optogenetic (Guo F. et al., Neuroscience Bulltin, 2022) and other functional imaging approaches (Malgorzata A. et al., JNeurosci, 2019 , Chrysostomidou L. et al., Neurobiol Pain, 2021) of neuronal activity finally allow researchers to get to the bottom of hyper-excitability in various tissues and discover new causative mechanisms. And these findings are hopeful developments for people who suffer from chronic pain. Let’s look at a recent example from researchers investigation diabetic pain syndromes:
Hypoxia-driven neuronal hyper-excitability
Neurons are interesting cell types, because despite lacking any energy storage, they require vast amounts of it, in the form of oxygen and nutrients. To perform their function, neurons need to be connected to a responsive vasculature (we’ve previously written about the dynamic role of neurovasculature in regulating neuronal activity). But what happens if supply cannot be guaranteed, for example when the vasculature is damaged by comorbidities, such as diabetes?
A connection between hyperexcitiability and a perturbed vasculature has previously been observed, but the mechanism remained elusive (Beazley-Long N. et al., Brain, Behavior, and Immunity, 2018)
However, recent work from researchers from the University of Nottingham, UK offer to finally shed a light on a new mechanism of chronic pain, induced by and mediated through hypoxia signalling.
- Hypoxia primer: In general, cells which suffer from a lack of oxygen supply response with activation of a transcriptional master-regulator, HIF1α, a protein that gets constantly produced and degraded by oxygen-sensitive processes. The moment cellular O2 levels drop, HIF1α becomes stabilized, trans-locates to the nucleus and springs to action, a process that takes mere minutes. HIF1α causes the overexpression of VEGF, CA7 and a hundreds of other hypoxia-inducible genes. Prolonged exposure to hypoxia causes HIF1α to completely remodel the cell and its microenvironment, switching energy production away from oxidative phosphorylation to glycosylation, shuts down energy-expanding processes and apoptosis, and instigates survival mechanisms. HIF1α based mechanisms are involved and contribute to disease progression in many different pathologies, from cancer to stroke to cardiovascular comorbidities, including diabetes (Review here)
In the figure below, the researchers used functional recordings from dorsal spine slice preparations from rats and induced hypoxia with a chemical compound (DMOG), which dramatically increased the neuronal firing rate of dorsal neurons. This is an exciting finding, as it suggest that the HIF1α signaling pathway is directly involved in remodeling the dorsal horn circuitry and regulation.
To further evaluate their hypothesis of hypoxia-induced chronic pain, the researchers in Nottingham used a type I diabetic mouse model with an inducible knock-out of the vascular endothelial growth factor (VEGF) gene. VEGF is a transcription factor that regulates angiogenesis, meaning the growth of blood vessels. Knockout of VEGF in the dorsal horn causes damage to the local microvasculature and capillary formation, reducing subsequent oxygen supply to these dorsal horn neurons. Long story short, these animals showed nociceptive behavioral hypersensitivity, as tested by exposing mice to heat (and seeing how long they take to move away). Even more remarkably, inhibition of CA7, an hypoxia-inducible gene partially responsible for the hypoxia-induced hypersensitivity, attenuated the phenotyp and allowed mice to persist longer again to heat pain stimulation, thus establishing this mechanism also on a behavioral axis.
Collectively, these experiments offer several remarkable findings.
This investigation demonstrates that induction of a hypoxic microenvironment in the dorsal horn, as occurs in diabetes, is an integral process by which neurons are activated to initiate neuropathic pain states. This leads to the conjecture that reversing hypoxia by improving spinal cord microvascular blood flow could reverse or prevent neuropathic pain — Da Vitoria Lobo M. et al., Pain, 2022
On the larger picture, connecting vascular degeneration, hypoxic microenvironments and neuronal hyper-excitability mechanistically offers a compelling framework to understand the complex interactions underlying chronic pain conditions in patients suffering from a wide range of comorbidities.
Understanding these complex interactions will allow researcher not only to develop new analgesic drugs, but might also open the door to preventative strategies, to attempt to stop chronic pain before it takes root.
Chronic pain is very common and often debilitating condition for individuals and a burden to the societies they are part of.
While pain is a complex phenomenon, new technologies and discoveries allow researchers to work towards a better understanding of the many interconnected physiological and pathological factors causing neuropathic pain, and offer new hope to affected patients.
Nature might have marked us to suffer, but it also made us smart enough to find ways to reduce pain as much as possible. With the tools of science, compassion and human ingenuity.
Roy M. et al., Eur J Pain, 2011
Bourinet E. et al., Physiol Rev., 2014
Beazley-Long N. et al., Brain, Behavior, and Immunity, 2018
Malgorzata A. et al., JNeurosci, 2019
Walters ET. et al., Phil. Trans. R. Soc., 2019
Nesse RM & Schulkin J., Phil. Trans. R. Soc., 2019
Finnerup NB et al., Physiological reviews, 2020
Chrysostomidou L. et al., Neurobiol Pain, 2021
Kocot-Kępska M. et al., MDPI, 2021
Da Vitoria Lobo M. et al., Pain, 2022
Guo F. et al., Neuroscience Bulltin, 2022
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Declaration of interest:
The author is an employee at 3Brain.