Dianne Lorton - US grants

Extensive studies from our laboratories have shown the presence of noradrenergic (NA) and substance P (SP) innervation of lymphoid organs. Numerous studies have reported that these neuro-transmitters can modulate immune functions. Conversely, Besedovsky and coworkers have shown that an immune response can alter neurotransmitter levels in reacting target lymphoid organs. We, and others, have evidence to support a role for NA and SP innervation of lymphoid organs in age-related immuno-suppression, and a variety of autoimmune disease models, such as experimental adjuvant- induced arthritis (EA). Both clinical studies of rheumatoid arthritis (RA) and experimental evidence of EA indicate involvement of NA and SP innervation in the pathophysiology of this disease. Clinical findings which are consistent with nervous system involvement in RA include: (1) a symmetric distribution of synovitis; (2) hemiplegic patients who later develop RA are spared the inflammatory process in joints on the paretic side; and (3) onset and exacerbation of the disease are often preceded by psychological trauma. It is well documented that NE and SP can modulate chronic inflammatory response and degree of destruction in the joints associated with RA and EA. Many experimental studies have employed systemic methods of denervation to demonstrate a role for these neurotransmitter systems, which would denervate several potential sites of action for these transmitters, including the joint, primary and secondary lymphoid organs, and central outflow to autonomic ganglia. Recently our laboratory has revealed that SP innervation of draining lymph nodes (LNs) is necessary for full expression of EA. This proposal further investigates the influence of NA and SP innervation of draining LNs in development and severity of EA in Lewis rats. Specifically, we propose to examine: (1) the effect of regional denervation of SP or NA innervation of popliteal and inguinal LNs on the expression of EA using chemical denervation, neurochemical analysis of SP and NE and assessing the time of onset, progression, and severity of EA in Lewis rats; and (2) the effect of EA and local inflammatory responses on NA and SP innervation of draining LNs, and subsequent immune responses in LNs, using double-label immunocytochemistry, neurochemical analysis of SP and NE, and beta-adrenoceptor and SP receptor binding assays. Functional studies will examine immuno-responsiveness of EA rats for correlation with neurochemical and anatomical measures of SP and NA innervation. These studies will provide a better understanding of the feedback circuitry involved in the development of EA, the functional consequences of EA in secondary lymphoid organs, and the role of SP and NA innervation during this disease processes. The ultimate significance of such studies lies in use of in vivo pharmacologic manipulation of neurotransmitters or neuromodulators that innervate lymphoid tissue, as a means of altering immune function and host defense, and the possible implications for development of therapeutive approaches for intervention of autoimmune diseases, such as RA.

[unreadable] DESCRIPTION (provided by applicant): Fibromyalgia (FM) is characterized by chronic pain, tenderness, and stiffness in skeletal muscle. FM afflicts 4 to 6 million people in the US, 80% of which are women. Chronic fatigue syndrome (CFS) is very similar to FM. About 75% of patients meeting the diagnostic criteria of CFS also meet the diagnostic criteria for FM. There is a linear increase in the prevalence of FM up to the eighth decade of life. Chronic pain in FM patients is not well managed in the clinic, severely affects their quality of life, and limits mobility and motor activities. We are proposing to establish a tissue bank to make brain and spinal cord tissue available to study FM. Further, we propose to use the collected spinal cord tissue to determine the extent to which chronic pain in FM patients is associated with glial activation and concomitant proinflammatory cytokine production. Glial activation is linked in animal models to pain facilitation. While studying rodent pain models has proven fruitful, there is a critical need to extend investigations from rodents to humans. Rodent studies predict that glial activation and glial proinflammatory products (e.g. tumor necrosis factor (TNF), interleukin-1 (IL-1) and IL-1B) will be key spinal mediators in human chronic pain. It is critical to test the extent that glia are involved in human pain regulation. It cannot be assumed based on animal data that glial activation and their proinflammatory cytokine products are associated with human chronic pain. Mechanisms of pain facilitation elucidated using animal models have at times proven disappointing when applied to human chronic pain. This is a critical problem because until this information becomes available, it will not be possible to develop drugs targeting glial activation or their inflammatory products for chronic pain treatment. The studies also will extend our knowledge of basic mechanisms in FM pain. The objectives of this application are 1) to increase enrollment of FM patients into the brain donation program at the Sun Health Research Institute (SHRI), collect relevant clinical data and to obtain blood, cerebrospinal fluid, spinal cords and brains from enrolled patients rapidly after death and 2) to determine the extent to which FM patients have glial activation or proinflammatory cytokine production in pain-processing areas of the brain and spinal cord using the tissue collected. These objectives will be fulfilled by completing the following Specific Aims: 1) we will actively recruit and enroll FM patients into the existing brain/spinal cord donation program at SHRI. 2) We will assess the extent to which there is immunohistochemical, mRNA or protein evidence of glial activation and proinflammatory cytokine production in spinal tissues of FM patients compared to age matched pain free controls. A research team that uniquely combines experts in pain research, FM, neurology, neuropsychology and personnel with extensive expertise with a neuroscience clinical research center and CMS tissue donation program have been assembled to complete these Aims. [unreadable] [unreadable] [unreadable]