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Summary Neuro‐immunology is becoming an increasingly important discipline of immunology. This review has examined the immunomodulatory function of one group of neuropeptides, the TK, particularly SP and NKA. These peptides are localized in primary afferent nerves which have been shown to innervate several immune organs. In addition, binding sites for the TK have been demonstrated in thymus, spleen and lymph node. Several immune cell types also express neurokinin receptors including human circulating lymphocytes with binding to the Th/i class predominating, murine T and B cells, a human T lymphoblastoid cell line, human monocytes, rabbit polymorphonuclear leucocytes and guinea‐pig macrophages. The apposition of nerves with immune cells and receptors for neuropeptides thus produces an environment for interaction between the nervous and immune systems. Studies in vitro and, more recently, in vivo have examined how the TK regulate immune cell responses. The TK stimulate proliferation of T cells, enhance mitogen‐induced release of cytokines including IFN‐γ, TNF‐α, IL‐1 and IL‐6 from mononuclear cells and macrophages, enhance immunoglobulin secretion and affect cellular chemotaxis and phagocytosis. Studies in vivo have shown a role for TK in lymphocyte recirculation of sheep lymph nodes, reversal of stress‐induced thymic involution and Ig production in both rat and mouse. Many of these effects appear to be mediated via NK‐2 type receptors. To date, most of the work has involved studies in vitro, but the results from these are now being validated by studies in vivo where both the immune system and neuropeptides are able to interact at many anatomical sites. The complexities of the immune and the nervous systems mean that only a small number of potential interactions has been examined. Future studies can be expected to amplify these observations, especially with respect to the understanding of inflammatory and immune diseases in humans.

Summary. Primary afferent iinmyetinated nerves modulate ihe intlammatory response to injury through a process known as neurogenic inflammation. The undecapeptide Substance P is contained in many of these nerves and therefore may be an important mediator of the response. Treatment of neonatal rats with capsaicin permanently destroys primary afferent unmyelinated nerves and depletes (he skin and other organs of Substance P. These animals have a reduced capacity to mount an inflammatory response to injury. We examined the ability of Substance P to chemo-attract neutrophils from normal rats and rats treated a.s neonates with capsaicin. Substance P was shown to cause normal rat neutrophils to chemotact at an optimum concentration of 5 x 10 -' ' M. Equivalent chemotaxis was observed in neutrophils from rats pretreated as neonates with capsaicin. Substance P did not increase chemokinesis. These in vitro results support the view that the reduced neurogenic inflammatory response seen in capsaicin-pretreated rats is not due to a direct toxic effect of capsaicin on neutrophils, but may be due to a decreased availability of neurally derived Substance P a£ the site of injury.

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1 Endothelin-1 and endothelin-3 enhanced concentration-dependently the rat vas deferens twitch response to electrical stimulation, endothelin-1 being three times more potent. Sarafotoxin S6c was at least 200 times less active than endothelin-1.2 The response to endothelin was antagonized in a competitive manner by the supposedly selective ETA receptor antagonist, BQ-123 (pA2: 7.0 ± 0.1). In contrast, the endothelin-I concentration-response curve was only shifted two fold in the presence of 1O JM BQ-123, while no effect was observed at 1 AM. 3 This evidence suggests the rat vas deferens contains an endothelin receptor not conforming to the ETA/ETB receptor subtype classification so far proposed.

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1 In the anaesthetized, ganglion-blocked rat, intravenous boluses of endothelin-1, endothelin-2 and endothelin-3 induced a transient hypotensive effect followed by a potent long lasting pressor response (ED_sommHg: 0.72 ± 0.05, 1.8 ± 0.2 and 2.7 ± 0.3 nmol kg-', respectively). The maximal effect for the three peptides was of a similar order of magnitude (,&MAP: 84 to 89 mmHg). Neither of these effects was influenced by phosphoramidon or thiorphan (10 mg kg-', i.v.).2 Intravenously administered big-endothelin-1 and -2 induced a transient (1-2 min) hypotension followed by a potent long lasting (>25 min) vasopressor effect (ED50,.Hg: 1.8 ± 0.2 and 6.7 ± 0.4 nmol kg-', respectively), with a similar maximal activity (A MAP: 85 ± 4 and 81 ± 2.4 mmHg, respectively). The onset of the big-endothelin-l vasopressor effect was more rapid (5-6 min) than that of big-endothelin-2 (10-13 min). Big-endothelin-3 was found to induce only a potent, long lasting (>35 min) hypertension, with a maximal effect of 75 ± 4.6 mmHg at 10 nmol kg-' and an ED50,,,,Hg of 6.5 ± 0.4 nmol kg-'. The onset of this effect was much slower (20-25 min) than that of the other proendothelins. Pressor responses induced by big-endothelin-1, -2 and -3 (3, 15 and 10 nmol kg-', respectively) were markedly reduced (60, 80 and 100%) in the presence of phosphoramidon (10 mg kg-', i.v.). Thiorphan (10 mg kg', i.v.) did not inhibit the effects of big-endothelin-1, -2 and -3. 3 In the electrically stimulated rat vas deferens, endothelin-I and -2 were found to be equipotent enhancers of the twitch response (EC,00%: 4.0 ± 0.4 nm and 7.9 ± 4.8 nm, respectively), both about 3-4 fold as active as endothelin-3 (EC,00%: 19 ± 2.5 nM). Endothelin-1 and -3 showed a comparable maximal stimulatory effect (Emax: 296 ± 30 and 262 ± 24%) while endothelin-2 was less active (Em,,: 194 ± 30%).4 Big-endothelin-l and -2 were potent enhancers of the twitch reponse too (EC 1o,%: 10.0 ± 2.6 nM and 21.6 + 3.2 nM, respectively), with a comparable maximal stimulatory effect (Ema: 254 ± 22 and 264 ± 24%). Big-endothelin-3 was found to be less potent (EC,0o%: 275 ± 21 nM), but retained a marked potentiating effect (Emax: 200 ± 38%). Phosphoramidon, but not thiorphan, concentration-dependently (10 and 100 JM) reduced big-endothelin-1 (58 and 86% respectively) and big-endothelin-2 (21 and 56%) -mediated responses. Conversely, the big-endothelin-3 effect was reduced by phosphoramidon only at 100#JM (-70%), while thiorphan acts concentration-dependently (31 and 71% at 10 and 100JIM respectively); thus, in the rat vas deferens, big-endothelin-I and -2 were as potent as their corresponding endothelins, while big-endothelin-3 was about 20 times less potent than endothelin-3. 5 The increasing effect of endothelin-2 (194 ± 30% over baseline) was significantly enhanced by either 10 JIM phosphoramidon (277 ± 42%) or thiorphan (318 ± 15%). The endothelin-I and endothelin-3-mediated twitch enhancement was not affected by the two protease inhibitors (10JIM). 6 These results suggest that in vivo big-endoth...