We have all experienced some kind of pain countless times throughout our lives; be it a small paper cut that stings for days, to the agony of a severely broken limb. Despite pain being an unpleasant and unwanted experience, it is vital for our survival and wellbeing. It acts as a danger signal, informing us of injury and damage.
What is Chronic Pain?
Pain is experienced after peripheral nociception, the physical process of detecting and transducing sensory signals in response to harmful stimuli. Nociceptive nerves send electrical impulses from the damaged site via a pathway called the spinothalamic tract, which eventually terminates in the sensory cortex of our brains. It is then that pain is perceived and experienced.
Problems arise when pain is continuously felt without the presence of harmful stimuli. This pain, known as chronic pain, no longer serves a protecting role and instead becomes pathological and debilitating. Chronic pain can arise after damage to the nociceptors transducing the signals in the periphery. This neuropathy can result in the unprovoked firing of nociceptive signals, despite the original injury having healed. Chronic pain can persist for months to years and so far has proven difficult to treat pharmacologically. Up until now, over the counter painkillers such as aspirin and narcotic analgesics such as morphine have been used in pain management. However, the efficacy of drug therapies vary for individuals and issues surrounding tolerance and addiction have limited their success. Over 10% of adults in the UK are affected by chronic pain and the debilitating, stressful nature of the condition has emphasized the requirement for newer, more effective treatments.
Recently, research surrounding the management of chronic pain has diverted from pharmacological intervention and instead has focused its efforts on specifically silencing individual peripheral nociceptors that become over active in chronic pain conditions. The current approved approaches include the use of the Botulinum toxin to suppress the secretion of chemical signals called neurotransmitters from nociceptors to inhibit pain signal transmission. This strategy, however, indiscriminately blocks peripheral nerves, hence lowering its efficacy as a pain management technique. In recent years, the emergence of Optogenetics as an approach to selectively target the nociceptors using light has overcome these previous drawbacks, and proves an exciting possibility for chronic pain treatment.
What is Optogenetics?
Optogenetics is the use of light to selectively control neural activity. Light activated protein channels, known as opsins, can be targeted to enhance or disrupt neuronal firing.
When exposed to a flash of light these channels open, allowing ions to enter the cell. Depending on the type of opsin used, positive or negatively charged ions will enter. The more positive ions inside a neuron, the more likely it is to fire and send signals to other neurons. The more negative ions inside, the less likely it is to fire.
In the context of (chronic) pain transmission, researchers believe nociceptors are hyper-excitable, uncontrollably sending nociceptive signals to the sensory cortex, resulting in constant pain. In order to reduce the frequency of signals, these neurons must be inhibited. This is where Optogenetics comes into play. By inserting an ‘off’ light sensitive channel into the nociceptor, the influx of negatively charged ions leads to hyperpolarization, suppressing its activity.
The first few attempts to control nociceptors using Optogenetics were successful yet limited to in vitro preparations rather than freely moving, living mice. Further technological advances meant neuroscientists could successfully insert the genes encoding for these opsins into mice genomes. The transgenic mice produced express these channels in their nerves as if they were their own. Scientists then induce pain conditions in these mice, and via light stimulation opsins are activated and pain perception is suppressed.
Since these attempts, the technique has come a long way. The use of viral vectors to deliver the opsin genes to the target nociceptors has made the technique more accessible and applicable to humans, without the need for transgenics. In a recent study, the viral delivery of Halorhodopsin successfully resulted in the inhibition of pain when exposed to light in freely moving mice (Iyer et al, 2014). Induced pain conditions such as hyperalgesia (increased sensitivity to pain) were reversed. A simple viral injection and flash of light relieved the suffering of constant pain.
Despite numerous animal studies yielding positive results, two major challenges limit the clinical application in humans – the light delivery method and opsin duration. Transdermal light activation avoids invasive procedures, however skin thickness and the need for constant illumination poses problems. So far, the use of short acting opsins has limited the technique to acute pain conditions only. If longer lasting opsins were used, more complex, chronic pain conditions could be targeted.
Recently this year, the sustained inhibition of nociceptors using transient transdermal light activation was achieved. In the 2016 study (Iyer et al, 2016), a newly developed inhibitory Channel rhodopsin (SwiChR) was inserted into the sciatic nerves of mice. The channel, with slow acting kinetics, leads to the persistent inhibition of pain long after the (blue) light activation. The inhibition is sustained over long periods without the need for constant illumination, something that has never been achieved before.
These significant findings take us one step closer to the clinical translation of Optogenetics as a pain management strategy in humans. Further research and improved technologies are needed before human application, and questions surrounding the longevity and practicality of Optogenetics require answers. For those suffering from chronic pain, new advances can’t come fast enough and Optogenetics proves an exciting new possibility for those with constant, untreatable pain.
Autor: Rachel Coneys
Editor: Molly Campbell
Action on Pain, 2015. About Chronic Pain [Online]. Available from: http://www.action-on-pain.co.uk
Iyer, S.M., Montogomery, K.L., Towne, C., Lee, S.Y., Ramakrishnan, C., Deisseroth, K., and Delp, S.L., 2014. Virally mediated optogenetic excitation and inhibition of pain in freely moving non-transgenic mice. Nature Biotechnology [Online]. 32(3): p274-278
Iyer, S.M., Vesuna, S., Ramakrishnan, C., Huynh, K., Young, S., Berndt, A., and Delp, S.L., 2016. Optogenetic and chemogenetic strategies for sustained inhibition of pain. Scientific Reports [Online]. 6:30570
Sim, W.S., 2011. Application of Botulinum Toxin in Pain Management. The Korean Journal of Pain [Online]. 24(1): p1-6