Our experiments identify critical actions of the EP1 receptor in acute, prostaglandin-dependent pain responses. In the acetic acid model, our studies indicate that inhibition of signaling through the EP1 receptor accounts for a major component of the effect of NSAIDs to ameliorate pain. Studies by Murata and colleagues using mice lacking prostacyclin receptors (IP) have also suggested that IP receptors play a large role in this response (29
). While the reasons for these differing results are not clear, variation in the genetic background of the mice is one factor that may contribute. Background genes have profound effects on the phenotype of other EP receptor–deficient mice (9
). However, if genetic background affects pain responses to prostaglandins, one must be concerned about potentially confounding effects caused by the mixed genetic background of the IP-receptor knockouts. By contrast, the EP1-deficient mice were produced on an inbred DBA/1lacJ background. Recent studies in which PGE2
and PGE analogues were microinjected into the rat ventromedial hypothalamus are also consistent with a role for EP1 receptors in the antinociceptive actions of PGE2
). Alternatively, it is possible that signals from both the EP1 and IP receptors are involved in the acetic acid response and that the absence of either receptor alone is sufficient to attenuate the response. The observation that IP and EP1 receptors are coexpressed in dorsal root ganglia provides theoretical support for this possibility (31
). Taken together, these data indicate that the EP1 receptor, along with IP receptors, are potential therapeutic targets for ameliorating inflammatory pain. There is a substantial body of evidence that supports a role for PGE2
in the regulation of blood pressure and vascular tone. Acute administration of PGE2
causes marked vasodilation, and these hemodynamic actions of PGE2
are probably most important for short-term regulation of blood flow. We and others have recently used gene targeting to define the relative roles of EP receptors in mediating the acute vascular actions of PGE2
). In these studies, the EP2 and EP4 receptors appeared to be the dominant mediators of vasodilation. However, there were substantial differences between males and females in the contributions of individual EP receptors to the vasodilatory response. In particular, the EP1 receptor appears to mediate vasodilation in males.
The chronic effects of PGE2
to influence blood pressure seem to be variable. Depending on the circumstance and mode of administration, chronic administration of PGE2
has been reported to either increase (33
) or reduce blood pressure in vivo (28
). However, over the long term, actions of PGE2
to influence sodium excretory mechanisms in the kidney should be a critical determinant in its actions to regulate blood pressure. In this regard, the EP1-receptor expression has been demonstrated in mouse, rat, rabbit, and human kidneys (36
). Our studies demonstrate a unique role for the EP1 receptor in blood pressure homeostasis since the absence of EP1 receptors is associated with significant reductions in blood pressure, especially in males. Furthermore, our data suggest that the absence of the EP1 receptor is associated with an inability to maintain normal extracellular fluid volume since pulse and plasma renin activity are elevated when the animals are fed a “normal” 0.4% sodium diet. The observation that there is an additional fall in blood pressure when the animals are fed a sodium-deficient diet is also consistent with actions of the EP1 receptor to promote sodium reabsorption in the mouse.
Evidence from a number of sources has suggested that mechanisms of blood pressure homeostasis might be quite different for males and females (40
). For example, in several models of hypertension, elevated blood pressure develops sooner and is more severe in males than females (42
). In addition, experimental studies in humans have identified significant differences between males and females in the relationship of sodium chloride intake to alterations in blood pressure (43
). Our findings suggest that the EP1 receptor may contribute to the sexual dimorphism in blood pressure regulation. This finding is also consistent with our previous studies demonstrating that the contribution of various EP receptors to the vasodilator actions of PGE2
differ between sexes (28
Inhibition of the COX pathway using gene targeting (18
) or pharmacological inhibitors have demonstrated the importance of prostaglandins, and specifically PGE2
, in mediating pain and/or inflammation (48
). We provide evidence supporting the role of the EP1 receptor in mediating pain and inflammation. The role of PGE2
on cardiovascular homeostasis is more complex and is still debated as reports suggest that it can act both as an antihypertensive or prohypertensive hormone. This is due in part to the different EP receptor–mediated signal-transduction pathways. We show that the absence of the EP1 receptor causes a significant decrease in systolic blood pressure in males, but not females, and that dietary sodium restriction exacerbates this male-specific hypotension. The reduction in blood pressure is accompanied by a compensatory increase in activity of the renin-angiotensin system. In conclusion, our data suggest that selective inhibition of the EP1 receptor might inhibit pain responses while also providing favorable cardiovascular effects.
In summary, the findings reported here suggest that the analgesic actions of NSAIDs in inflammatory pain, especially visceral stimuli, are mediated to a significant degree by inhibition of signaling through the EP1 receptor. Moreover, the absence of EP1 receptors does not cause abnormalities in kidney structure and results in a lowering of resting blood pressure. Accordingly, these data identify the EP1 receptor as a selective target for therapies that would possess the analgesic effects of NSAIDs without adverse effects on the kidney.