We propose that afferent plasticity at their peripheral and central terminals plays a critical role in chronic neuropathic pain, expressed as allodynia, after SCI. A?-LTMRs, a group of small diameter myelinated afferents that innervate the hairy skin, have recently been shown to signal directionality of touch. They can be identified by their expression of the BDNF receptor, TrkB. A?-LTMRs require BDNF-TrkB signaling for normal mechanosensory functions. BDNF and TrkB are implicated in many adaptive and maladaptive processes, including pain. However, it is not clear what role they play in neuropathic pain after SCI. We hypothesize that maintained maladaptive peripheral plasticity involving BDNF-TrkB signaling produces hyperexcitability of A?-LTMRs, in turn lead to at-level pain after SCI. In fact, we propose that SCI transforms A?-LTMRs into allodynia-encoding nociceptors in dermatomes adjacent to the injury and that this transformation is in part due to the immense spatial and temporal plasticity SCI imposes on BDNF-TrkB signaling. The proposed study consisting of 3 specific aims will be done in transgenic mice which will enable us to selectively target TrkB-expressing A?-LTMRs, in intact subjects and after T10 moderate to severe contusion SCI. In SA 1, electrophysiological studies using the ex-vivo skin-nerve, in-vitro adult mouse model and spinal slices with attached dorsal roots in TrkB::ChR2 mice will assess SCI effects on A?-LTMRs recruitment, firing and synaptic responses. We will also examine SCI-induced expansion A?-LTMRs? receptive field, as a potential outcome of peripheral afferent sprouting (SA 2). SA 2 will examine anatomical and neurochemical plasticity of A?-LTMRs, and changes in BDNF and TrkB expression in the spinal cord, skin and DRG. SA 3 will employ behavioral tests to investigate A?-LTMRs? role in the development of at-level mechanical allodynia after SCI using modified place escape/aversion paradigms, and measures of audible and ultrasonic vocalizations following mechanical and optical stimulation. We will also incorporate novel ultrasensitive movement detection sensors for continuous monitoring of respiratory rates, which is a measurable index of sympathetic arousal that may also be indicative of pain. This innovative and clinically-relevant study will be the first to identify A?-LTMR plasticity as a neural mechanism of at-level mechanical allodynia after SCI and that peripheral plasticity mediates the transformation of cutaneous touch afferent into nociceptors. The results obtained from this study will increase our knowledge of the neurophysiological mechanisms that underlie maladaptive sensory processing and pain after SCI.
Title: Examining the roles A-delta LTMRs and BDNF signaling play in neuropathic pain after SCI The project proposes that peripheral mechanisms such as afferent sprouting and expansion of receptive fields are pivotal to maintained neuropathic pain, including allodynia, after spinal cord injury. Experiments combining electrophysiology, behavioral and molecular tools will investigate how a subpopulation of cutaneous touch afferents known as A?-LTMRs, and maladaptive BDNF-TrkB signaling mediate neuropathic at-level pain after SCI.
