A new approach to measuring chronic pain

Chronic pain is an extremely debilitating condition which affects almost half of the adult population in the UK. Commonly caused by inflammatory diseases or tissue damage, chronic pain patients not only experience persistent pain, but also have a high incidence of depression and anxiety, which further decrease their quality of life. Current therapeutic strategies frequently focus on alleviating pain, rather than treating the underlying cause, but are often ineffective at this and/or cause a number of unwanted side-effects. There is therefore an interest in understanding the neural basis of chronic pain in order to develop better drugs.

Studying complex physiological processes, such as pain, often involves the use of animals. Animal research is incredibly valuable to scientists and every effort is made to reduce the pain, suffering and distresses experienced by animals in accordance with the 3Rs principles (replacement, reduction and refinement) of animal use. Historically, the level of pain experienced by animals during inflammation is assessed by measuring behavioural responses to the application of additional painful stimuli, such as heat or mechanical pressure; these are similar to tests conducted on human patients at pain clinics when assessing their symptoms. Similar to humans, animals experiencing inflammatory pain are expected to be more sensitive to the additional pain and therefore withdraw their paw or react earlier and/or to weaker stimuli compared to those not experiencing inflammation. These approaches, while widely accepted, are often criticised because they cause additional pain to animals during testing and do not model the spontaneous nature of pain that reduces the wellbeing of arthritic patients.

Therefore, a recent study led by Gates Cambridge Scholar Sampurna Chakrabarti* [2016], along with other members of Dr Ewan St. John Smith’s lab, focussed on changes in ethologically relevant or ‘normal’ rodent behaviours, such as burrowing, digging and nest building. A reduction in these behaviours is comparable to the reduced motivation towards daily activity observed in chronic pain patients and does not cause any additional suffering in mice. The digging activity of mice was assessed before and after induction of inflammation by placing them into cages (similar to those normally used to house laboratory mice) with heavily packed bedding material to a depth of ~4 cm. Mice were filmed for three-minutes in the test cage, after which the time each mouse spent digging and the number of digging sites were recorded. This approach, although incredibly simple, can capture both the heightened pain sensitivity (mice dig less due to pain experienced during digging), as well as the emotional aspect of pain (animals experiencing pain are likely less willing to dig due to general apathy). We  found that inflammatory knee pain decreases natural digging behaviour in mice. This method is much more representative of the on-going and spontaneous pain reported by chronic pain patients and therefore results are far more likely to correlate with clinical trials in humans, which could speed up the development of remedies for inflammatory pain. At the neuronal level, pain was manifested by an increased excitability of knee neurons along with an increase in expression of TRPV1 – a protein found in nerves that responds to capsaicin, the substance that gives chilli peppers their hot sensation, as well as responding to heat and acid.

One of the newer drug categories being explored for inflammatory pain is TPRV1 antagonists. To test if this drug class can also alleviate spontaneous joint pain we assessed the digging behaviour of a separate cohort of mice before and after induction of inflammation and then again after the mice were administered with a TRPV1 antagonist. As expected, mice dig less after the induction of knee inflammation, but, digging returns to pre-inflammation levels following administration of the TRPV1 antagonist. This result adds to a body of evidence implicating TRPV1 antagonists as strong contenders for the next generation of pain medication.

*This article was written by Luke Pattison, Dr Ewan Smith and Sampurna Chakrabarti. Sampurna is doing a PhD in Pharmacology. She  presented this work as a Trainee Professional Development awardee (along with the support from Gates Cambridge academic development fund) at the Society for Neuroscience (SfN) Annual meeting (San Diego, 3-7th November, 2018). The poster was well-received at this conference, which is one of the largest congregations of neuroscientists globally, and was covered by the SfN blog. Picture credit: Wikipedia.