Tachykinin receptor modulators: novel therapeutics for rheumatoid arthritis

The activation of a cellular immune response in a genetically susceptible individual is widely recognised as a main step in triggering rheumatoid arthritis (RA). The tachykinins, substance P (SP) and neurokinin A (NKA), can play a major role in different immune diseases. In patients with inflammatory joint disease, elevated levels of SP have been demonstrated in the synovial fluid of affected joints. It is well known that SP and, to a lesser extent, NKA are deeply involved in the processing of nociceptive signals and exert many pro-inflammatory actions, which may be elicited by an increased neuronal neurokinin release in arthritis; the mechanism behind this increase remains to be fully elucidated. Different observations suggest that one approach to the treatment of RA might be to inhibit the local effects of neurokinins in the affected joints. This review will summarise the more relevant aspects of this topic.     

Effects of tachykinins on uterine smooth muscle

1. Sensory nerves supplying the mammalian uterus have been shown to contain substance P (SP) and neurokinin (NK)A. This review presents some of the advances that have led to a greater understanding of the effects of tachykinins on uterine smooth muscle. 2. The cell-surface peptidase neprilysin (EC.3 24.11, endopeptidase 24.11, enkephalinase, CALLA, CD10) has been shown to play a major role in regulating the actions of tachykinins on both rat and human myometrium. Because this peptidase is known to be regulated by steroids and pregnancy, its effects may be of physiological relevance. 3. Tachykinins produce contractions of isolated myometrial preparations from non-pregnant rats and mice. The NK2 receptor mediates these effects in rat uterus, while the NK1 receptor may mediate these effects in the mouse uterus. 4. The effects of tachykinins have been examined on myometrial preparations obtained at Caesarean section from near-term pregnant women. In the presence of the peptidase inhibitors (thiorphan, captopril and bestatin), the mammalian tachykinins SP, NKA and NKB produced concentration-dependent uterine contractions. 5. The order of agonist potency NKA > SP = NKB suggested that NK2 receptors mediate uterine contractions in the human. This was confirmed using the stable analogues [Sar9,Met(O2)11]SP, [Lys5MeLeu9Nle10]NKA(4-10) and [N-MePhe7]NKB, which are NK1, NK2 and NK3 receptor selective, respectively. Only [Lys5MeLeu9Nle10]NKA(4-10) produced concentration-related contractions of human uterine smooth muscle. 6. The experimental findings described in the present review, taken together with results published previously in the literature, indicate that tachykinin peptides may play a physiological or pathophysiological role in regulating uterine smooth muscle activity. However, more extensive research will be required to confirm such a role for these peptides.