Chronic pain is a major public health epidemic, affecting more than 50 million Americans, and is one of the most frequently cited reasons that patients seek health care services. Unlike acute pain, which can be effectively treated using standard analgesics, chronic pain is a pathological nervous system disorder that persists for months or years. There are no effective treatments for this disabling condition, and the cellular and molecular mechanisms underlying it are poorly understood. The purpose of this study is to investigate one possible cellular mechanism, changes in Brain-Derived Neurotrophic Factor (BDNF) signal transduction in the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM), on the development and persistence of pain in an animal model. The discovery of a descending modulatory pathway from the brainstem to the spinal cord that can both reduce (inhibit) and enhance (facilitate) the perception of pain has led to the belief that chronic pain may arise from a long-term loss of inhibition or enhancement of facilitation, both of which involve synaptic transmission and plasticity. Similar types of plastic changes also occur during learning and memory by a process known as long term potentiation (LTP). A key regulator of LTP is BDNF, which exerts its effects by activating the tyrosine kinase receptor trkB. The trkB locus also produces a truncated receptor (T1) that inhibits BDNF signaling. The strength of the BDNF signal can be modulated at the cellular level by adjusting full-length and truncated trkB isoform expression, which leads to changes in synaptic efficacy. Both BDNF and trkB isoforms are expressed in the PAG and RVM, and there is evidence that supraspinal administration of exogenous BDNF can produce changes in nociception. The mechanisms underlying the BDNF effect are not well understood, however, and it is unclear whether BDNF signaling produces analgesia or increases nociception. Because trkB could be an important therapeutic target for the treatment of pain, we propose to examine whether the expression of trkB receptor isoforms are dynamically regulated in the PAG and RVM in response to persistent inflammation in the mouse. In addition, we will directly test whether changing BDNF signal strength results in a change in nocifensive behavior due to modulation of the descending pathway. These studies will provide important information regarding a potential role for BDNF in supraspinal descending modulation of pain. ? ?
| Dorsey, Susan G; Lovering, Richard M; Renn, Cynthia L et al. (2012) Genetic deletion of trkB.T1 increases neuromuscular function. Am J Physiol Cell Physiol 302:C141-53 |
| Renn, Cynthia L; Leitch, Carmen C; Dorsey, Susan G (2009) In vivo evidence that truncated trkB.T1 participates in nociception. Mol Pain 5:61 |
| Renn, Cynthia L; Lin, Lu; Thomas, Sharon et al. (2006) Full-length tropomyosin-related kinase B expression in the brainstem in response to persistent inflammatory pain. Neuroreport 17:1175-9 |
