Stress and inflammatory disease: widening roles for serotonin and substance P

Serotonin has been implicated in mediating the hypothalamo-pituitary-adrenal (HPA) axis response to stress and is an important therapeutic target for a number of psychiatric disorders including depression. The neurokinin substance P has been shown to inhibit stress-induced HPA axis activity and we have demonstrated that endogenous substance P is able to reduce the duration of the HPA axis response to stress suggesting an important role in the termination of the stress response. This may be important in controlling the transition from acute to chronic stress and substance P has recently attracted attention as a potential antidepressant.In addition to these central effects, serotonin and substance P are considered to be pro-inflammatory agents. Despite being implicated in mediating inflammation there have been few studies investigating the effects of manipulations of serotonergic or substance P systems on chronic inflammatory disease. Treatment of rats with adjuvant-induced arthritis(AA), a model of chronic inflammatory stress, with a substance P antagonist specific for the NK1 receptor subtype resulted in a reduction in hind paw inflammation suggesting substance P may influence inflammation. We have noted that depletion of whole body serotonin and selective central depletion of serotonin results in a decrease in the severity of inflammation in rats with adjuvant arthritis. Furthermore, treatment with a selective serotonin reuptake inhibitor results in an earlier onset and increased severity of inflammation in adjuvant arthritis, confirming a pro-inflammatory role for serotonin. Serotonin is also present in the immune tissues and concentrations in the spleen fall following the development of inflammation in adjuvant arthritis. Concentrations of serotonin are significantly higher in normal female spleen than in males, and this may underlie the greater predisposition of females to certain autoimmune diseases.There is increasing evidence of a role for transmitters such as serotonin and substance P,both centrally and peripherally, in mediating a wide variety of inflammatory and psychiatric disorders. A better understanding of the mechanisms of action of these transmitters and the development of suitable drugs targeting specific receptor subtypes has great potential to impact on clinical practice in the near future. The purpose of this review is to consider the separate roles of serotonin and substance P in relation to HPA axis stress responses, in the context of a model of chronic inflammatory disease, highlighting novel directions of current research for each of these transmitters.