Hawon Cho

Background: Various pathological conditions such as inflammation or injury can evoke pain hypersensitivity. That represents the response to innocuous stimuli or exaggerated response to noxious stimuli. The molecular mechanism based on the pain hypersensitivity is associated with changes in many of ion channels in dorsal-root ganglion (DRG) neurons. Anoctamin 1 (ANO1/TMEM16A), a Ca ²⁺ activated chloride channel is highly visible in small DRG neurons and responds to heat. Mice with an abolished function of ANO1 in DRG neurons demonstrated attenuated pain-like behaviors when exposed to noxious heat, suggesting a role in acute thermal nociception. In this study, we further examined the function of ANO1 in mediating inflammation- or injury-induced hyperalgesia or allodynia. Results: Using Advillin/Ano1 ^fl/fl ( Adv/Ano1 ^fl/fl ) mice that have a functional ablation of Ano1 mainly in DRG neurons, we were able to determine its role in mediating thermal hyperalgesia and mechanical allodynia induced by inflammation or nerve injury. The thermal hyperalgesia and mechanical allodynia induced by carrageenan injection and spared-nerve injury were significantly reduced in Adv/Ano1 ^fl/fl mice. In addition, flinching or licking behavior after bradykinin or formalin injection was also significantly reduced in Adv/Ano1 ^fl/fl mice. Since pathological conditions augment nociceptive behaviors, we expected ANO1's contribution to the excitability of DRG neurons. Indeed, the application of inflammatory mediators reduced the threshold for action potential (rheobase) or time for induction of the first action potential in DRG neurons isolated from control ( Ano1 ^fl/fl ) mice. These parameters for neuronal excitability induced by inflammatory mediators were not changed in Adv/Ano1 ^fl/fl mice, suggesting an active contribution of ANO1 in augmenting the neuronal excitability. Conclusions: In addition to ANO1's role in mediating acute thermal pain as a heat sensor, ANO1 is also capable of augmenting the excitability of DRG neurons under inflammatory or neuropathic conditions and thereby aggravates inflammation- or tissue injury-induced pathological pain.

Background: The quantification of pain intensity in vivo is essential for identifying the mechanisms of various types of pain or for evaluating the effects of different analgesics. A variety of behavioral tests for pain measurement have been devised, but many are limited because animals are physically restricted, which affects pain sensation. In this study, pain assessment was attempted with minimal physical restriction, and voluntary movements of unrestrained animals were used to evaluate the intensities of various types of pain. Results: The number of times animals reared or total distances traveled was measured using a motion-tracking device and found to be markedly reduced in carrageenan-induced inflammatory, acetic acid-induced visceral, and streptozotocin-induced neuropathic pain tests. These two voluntary movement parameters were found to be highly correlated with paw withdrawal latency from irradiating heat. In addition, these parameters were markedly reversed by morphine and by non-steroidal anti-inflammatory drugs in inflammatory pain models. These parameters were also useful to detect hypoalgesia in TRPV1^−/− mice. Conclusions: These results suggest that parameters of voluntary movement, such as, number of rearing and total distance moved, are effective indicators of pain intensity for many types of pain and that they can be used to evaluate degree of pain perception.