When we feel pain in response to an injury or infection it is the result of messages sent from pain sensors in the outer areas of the body to the brain. These pain sensors – called nociceptors – often lie beneath the skin and detect and signal the presence of tissue-damaging forces or the existence of tissue damage. One particular nociceptor, known as vanilloid receptor-1 (VR1), transmits sensory messages to the brain in response to thermal and painful chemical stimuli and is generally regarded as the major pain sensor.
In conditions such as arthritis or infection, the tissue involved at these sites becomes acidic. While normal human tissue has a neutral pH of approximately 6.5 – 7.5 (similar to water), a condition called tissue acidosis can cause a drop in cellular pH below 6.0 closer to that of household vinegar. When the cellular environment becomes acidic, both VR1 and a second nociceptor – acid sensing ion channels (ASICs) – are activated.
In previous experiments in mice, scientists have found that the activation of VR1 requires extremely severe tissue acidification – pH less than 6.0. This suggests that another pain sensor plays a role in nociception, specifically at pH levels greater than 6.0. Despite experimental data revealing that mouse brain cells lacking ASICs are severely lacking in their responses to acidic stimuli, controversy remains about the function of ASICs in mammals.
In a study reported in the October 21 issue of the Journal of Clinical Investigation (JCI) by Shinya Ugawa and colleagues from the Nagoya City University Medical School, Japan, the authors demonstrated that both VR1 and ASICs are involved in the sensing of acid-evoked pain in humans and that each type of nociceptor mediates this pain perception at very specific pH ranges.
The authors infused solutions of varying pH levels under the skin of the underside of the upper forearm of healthy male volunteers who were subsequently asked to estimate the intensity of the induced pain on a 0-10 scale. To determine which particular nociceptor was activated at each pH level, the authors systematically blocked ASICs-mediated pain perception with the ASICs inhibitor amiloride or VR1-mediated pain perception with the VR1-inhibitor capsazepine and then recorded the intensity of pain indicated by the subject in response to the solutions of various pH. Ugawa and colleagues found that amiloride potently blocked pain induced by solutions with a pH greater than 6.0, while capsazepine did not. At pH levels below 5.0, amiloride was less effective in reducing pain and capsazepine had a partial blocking effect.
These results demonstrated that ASICs, and not VR1, function as acid sensors within the pathophysiologically relevant pH range 6.0 – 7.2, and that the ASICs inhibitor amiloride may be a useful analgesic for the treatment of localized pain within this range.