The Actions of Sensory Neuropeptides on the Synovial Vasculature of Normal and Inflamed Joints

Inflammation of the joint, arthritis, is a major problem in human society, affecting large numbers of individuals, including a large number of those aged 60 and over. A principle event in development of inflammation is an increase in blood flow. Different factors are involved with neurocirculatory control of which the neurokinins and calcitonin gene-related peptide (CGRP) may have an important role and the work described in this thesis is directed at investigating this. There are few reports about the role of neurokinins in joint inflammation and how neurokinin receptors are affected and thus animal models of inflammation were used for these investigations, based on the rat knee joint. Two techniques were used to measure joint inflammation; a) microturbidimetry was used to examine knee joint perfusate to evaluate its protein content due to the extravasation effect of CGRP. b) laser Doppler imaging (LDI) was employed to give an estimate of blood flow changes in response to application of neurokinins In normal knee joints: 1) Intra articular injection of 10-6 mol of CGRP produced protein extravasation which was sustained throughout the period of infusion. This was a specific effect of CGRP and not merely a consequence of its potent vasodilator effect. 2) SP on its own induced a dose dependent and transient vasodilatation, this being mediated via NK1 and NK2 receptors. 3) NKA at higher doses induced vasodilatation and this vasodilator effect was chiefly mediated via NK2 receptors and a smaller part mediated via NK1 receptors. 4) NKB produced a potent and significant vasodilatation. This effect was mediated chiefly via NK1 and NK2 receptors and it is unlikely that NK3 receptors are present. 5) The neurokinin receptors in the rat knee joints are of the B type of NK2 and a possible subtype of NK1 receptors. 6) SP and perhaps other neurokinins are normally released from sensory nerves mediating and participating in regulation of vascular tone and basal blood flow. B) In inflamed knee joints: 1) In the carrageenan-induced inflammation, there is a hypersensitivity to the neurokinin response with a significant increase in SP- induced vasodilatation. 2) In the acute capsaicin treated knee, an acute vasoconstriction occurred at different doses of capsaicin which in lower doses was followed by a vasodilatation which could be due to release of neurokinins from sensory nerve endings. Vasoconstriction by 2% capsaicin is irreversible over the time course of the experiments. 3) With acute and chronic inflammation induced by capsaicin, there is an alteration in the response to neurokinins and there is an attenuated response to the SP vasodilator effect on blood flow. 4) In adjuvant-induced arthritis, one week post induction the effect of SP was completely abolished with no response to SP at any dose. This attenuation changes to a vasoconstriction effect at week 3. 5) There is a contralateral effect of adjuvant-induced arthritis, the response to SP being significantly attenuated in the contralateral knee. This response revealed a neurogenic effect of inflammation in one knee being exerted on the contralateral joint. 6) In all three different models of inflammation, the response to the neurokinins was altered but there was not any change to the 5HT and adrenaline response in adjuvant-induced inflammation. 7) In all of these three models of inflammation neuropeptides have a key role in initiating of the signs of inflammation. The further joints changes will depend on the nature of the inflammatory agent and individual treatments would be required to reduce inflammation and joint damage