The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
The newly discovered peptide substance K (SK) is an aliphatic tachykinin structurally related to the aromatic tachykinin substance P (SP). Immunohistochemical examination showed a close association between SK afferents and dopamine (DA) cell bodies. Examination of the possible role of SK in modulating midbrain DA systems revealed that SP, but not SK, is associated with the stress response of the mesocortical system. Ventral tegmental area injections of SK effected locomotor hyperactivity, a mesolimbic-mediated behavior. Ventral tegmental injections of SP, but not SK, activated DA metabolism in the prefrontal cortex, while SK injections altered DA metabolism in the nucleus accumbens, but not the cortical site. These data suggest that SK and SP may differentially modulate the mesolimbic and mesocortical systems.
A comparison was made between substance P (SP) and substance K (SK) in the ventral tegmental area (VTA) (A10 dopamine cell group) of the rat. Approximately equal densities of SP and SK-immunoreactive neuronal fibers were observed. However, while previous reports demonstrate negligible density of autoradiographically defined SP receptors in the VTA, we observed a high density of SK receptors. SK or SP was microinjected into the VTA, and changes in spontaneous motor activity were measured using a photocell apparatus. SK was found to be at least 10 times more potent than SP in producing an increase in motor activity. These data suggest that while both SK and SP are present in the VTA, SK may have a more significant physiological role in modulating dopamine neurons in the ventromedial mesencephalon.
Corticotropin-releasing hormone (CRH), the principal regulator of the hypothalamic-pituitary-adrenal axis, is also secreted in peripheral inflammatory sites, where it acts as a local proinflammatory agent. Arthritis-susceptible LEW/N rats have profoundly deficient hypothalamic CRH responses to inflammatory stimuli and other stressors. Arthritis-resistant F344/N rats, on the other hand, have a robust increase in hypothalamic CRH in response to the same stimuli. Contrasting with these hypothalamic CRH responses, we now show that CRH expression is markedly increased in the joints and surrounding tissues of LEW/N rats with streptococcal cell wall- and adjuvant-induced arthritis, whereas it is not increased in similarly treated F344/N rats and is only transiently increased in congenitally athymic nude LEW.rnu/rnu rats. Glucocorticoid treatment suppressed, but did not eliminate, CRH immunoreactivity in the joints of LEW/N rats. CRH mRNA was present in inflamed synovia, as well as in spinal cord, and inflamed synovia also expressed specific CRH-binding sites. We compared CRH expression in inflamed joints with another well-characterized proinflammatory neuropeptide, substance P (SP), and found that SP immunoreactivity paralleled that of CRH. In summary, although LEW/N rats have deficient hypothalamic CRH responses to inflammatory stimuli compared with F344/N rats, they express relatively high levels of CRH at the site of inflammation. Analogous to SP, CRH may be delivered to the inflammatory site by peripheral nerves and/or synthesized at the inflammatory site. These data provide further support for the concept that CRH not only triggers the pituitary-adrenal antiinflammatory cascade, but also functions as an antithetically active local mediator of acute and chronic inflammatory arthritis. These data also illustrate the complex interrelationships of the nervous, endocrine, immune, and inflammatory systems.