In Vivo Patch Clamp Studies of Dorsal Horn Neurons in Relation to Headache

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DESCRIPTION (provided by applicant): Nociceptive neurons in the medullary dorsal horn that receive convergent input from dural and facial receptive fields have been implicated in mediating the pain of some types of headache, including migraine. These neurons can be induced into a prolonged state of sensitization, or abnormally heightened responsiveness, following an initial noxious sensory input from the dura. The phenomenon of central sensitization of dorsal horn nociceptive neurons is thought to contribute to clinical pain conditions, and has now been implicated as a critical factor in the pain and allodynia of migraine. Consequently, the study of central sensitization and the resulting allodynia has become a major focus of current headache research. However, our understanding of the electrophysiological mechanisms of central sensitization is derived in large part from in vitro slice studies, which have the limitation that it is not possible to characterize responses to natural forms of peripheral stimulation, or stimulate specific types of peripheral tissues. As a result, there is a gap that must be bridged in trying to relate the information obtained from in vitro studies to the phenomenon of central sensitization as observed in vivo. The novel technique of in vivo patch clamp recording has the potential to help bridge this gap, and in so doing have a major impact on our understanding of central nociceptive processing. Among the advantages of this technique over extracellular recording are the ability to directly detect inhibitory and subthreshold excitatory synaptic inputs, and the ability to separately measure inhibitory and excitatory inputs in isolation. We propose to establish this technique for the first time in the brainstem trigeminal system, and use it to examine receptive field properties and sensitization of nociceptive medullary dorsal horn neurons that receive input from the intracranial dura. We propose that the responsiveness of these neurons represents a balance between the strength of inhibitory and excitatory inputs, and that this balance is altered during central sensitization. We also propose that conversion of subthreshold to suprathreshold inputs represents an important underlying mechanism of sensitization. We hypothesize that the modulatory mechanisms that operate in these neurons differ from those in neurons that receive input only from a superficial site such as cornea, and these differences will be important for understanding the distinctive qualities of headache pain and the pathogenesis of migraine. PUBLIC HEALTH RELEVANCE This project will give new insight into the cellular mechanisms underlying the phenomenon of central sensitization of pain-transmitting neurons, which is now thought to be an important component of migraine as well as many other pain conditions. This information will lead to better understanding of migraine headache, and will be important for devising strategies for development of new drug treatments.