Characterization of the Circadian Rhythm of Pain in Naive and Neuropathic Mice
Neuropathic pain is defined as “pain caused by a lesion or disease of the nervous system”. Neuropathic pain conditions are estimated to affect up to 8% of the population worldwide and presently, the most common treatment strategies are often ineffective. Opioids, for example, are a “last effort” treatment which, when used properly, are only effective at reducing pain, on average, by 20-30%. Treatment with opioids however, is problematic not only because of the large number of side effects but also because of the high risk of developing tolerance and/or addiction. Thus, new therapeutic options are required to treat neuropathic and other chronic pain conditions. Clinical studies have recently demonstrated that patients with chronic neuropathic pain often exhibit circadian fluctuations in pain intensity, with patients reporting significantly higher levels of pain in the evening than during the day. We therefore sought to understand whether a link exists between circadian rhythms and somatosensory activity using a mouse model. To this end, we used standard behavioural assays to measure mechanical and thermal sensitivity in both male and female, naïve and nerve-injured C57BL/6J mice at different times of the day. We found a circadian pattern only in the heat sensitivity of naïve animals, with mice displaying a higher sensitivity at 9am than at 9pm. Pharmacological characterization of this pattern by intraplantar injection of capsaicin suggests that the observed rhythm may be modulated by the transient receptor potential vanilloid 1 (TRPV1) ion channel, as mice displayed a higher level of sensitivity when injected at 9am than at 9pm. Nerve-injured males were found to display a circadian rhythm in mechanical sensitivity (they were more sensitive at 9am than at 9pm), while the female data remains inconclusive. These results provide evidence that mice display a modality-specific circadian rhythm of pain. Future studies will be required to expand on these findings and to elucidate the mechanisms underlying the circadian control of pain, both naïve and after injury. The robust rhythm observed, however, does provide a foundation upon which future studies can build, with the hope of translating this research from bench to bedside.