Sensory nerve terminals are packed with mitochondria. Multiple environmental stimuli, including inflammation, regulate mitochondrial function. Mitochondria modulate cellular signaling via production of ATP and reactive oxygen species (ROS) and the regulation of Ca2+ fluxes. We have found that mitochondrial signaling selectively activates nociceptive sensory nerves. These responses were dependent on the nociceptive ion channels transient receptor potential (TRP) ankyrin 1 (A1) and TRP vanilloid 1 (V1). Furthermore, mitochondrial signaling also independently caused an increase in nociceptive sensory nerve excitability. This hyperexcitability was not dependent on TRPA1 or TRPV1 but instead was due to the activity of protein kinase C.

Transient receptor potential ankyrin 1 (TRPA1) is a polymodal cation channel expressed on a subset of nociceptive sensory nerves. Best known as the ‘wasabi detector’, TRPA1 is activated by a host of environmental and inflammatory stimuli. We have previously characterized TRPA1 as the molecular mechanism underlying nociceptor activation by the environmental pollutants ozone and toluene diisocyanate and numerous products of inflammation and oxidative stress including 4-hydroxynonenal, prostanoids and 9-nitrooleate. These molecules activate TRPA1 via covalent modification of specific cysteine residues on the channel. We have recently shown that these particular cysteines demonstrate exceptionally high reactivity, thus accounting for their role in noxious stimuli detection.

Fundamentally, sensory nerve function can be most generally described by three parameters: what the nerve detects; where in the body is the sensor; and what CNS circuits are regulated by the nerve activity? Using state-of-the-art genetic tools, we are investigating the specific neural pathways that connect specific sensory subsets to the CNS. In this way we are mapping the sensory arm of the peripheral nervous system.

Oxygen consumption by working tissues (e.g. brain, muscles) is linked with blood flow. As such the CNS integrates the control of the respiratory and cardiovascular physiology. Part of this integration are reflexes initiated from the airways which can impact cardiovascular function. This may be harmless in healthy individuals, but represents a major risk factor for individuals with preexisting cardiovascular disease. We have recently shown that inhalation of nociceptive stimuli cause chaotic slowing of heart rhythms (bradycardia) due to reflex stimulation of cardiac parasympathetic nerves downstream of airway nociceptive signaling. We are interested in understanding how preexisting cardiovascular function modulates these pulmonary-cardiac reflexes.