J. Clin. Invest. 108: 25–30 (2001). DOI: 10.1172/JCI200113455. product of lipid peroxidation, results in activation of distinct, as well as overlapping, signaling pathways (4). The existence of four subtypes of the receptor for PGE2 is remarkable, given that the other prostanoids each have only a single receptor. The homology of amino acid sequences between different types of the receptors within each functional group is much higher than that found among the four PGE receptor subtypes. The phylogenetic tree derived from receptor homologies indicates that prostanoid receptors originated from the primitive PGE receptor, from which the subtypes of the PGE receptor then evolved. Other PGs and Tx receptors subsequently evolved from functionally related PGE receptor subtypes by gene duplication. This evolutionary history suggests that the different paralogues play distinct physiological roles. The roles of PGs in various physiological and pathophysiological processes have thus far been suggested by comparing the effects of aspirin-like drugs with those of each prostanoid added exogenously. However, such studies do not clearly indicate which type of prostanoid and which class of prostanoid receptor is involved in a given process, nor how critical the actions of prostanoids might be. To address these questions, we and others have generated and analyzed mice deficient in each prostanoid receptor. The reported findings of these knockout mice are summarized in Table 1. Here we discuss the significance of some of these findings. Inflammation and pain. Vasodilation and pain generation are two classic features of acute inflammation to which prostanoids appear to contribute. Aspirin-like drugs suppress these responses, and PGE2 and PGI2 can mimic these actions. Murata et al.(5) employed carrageenan-induced paw swelling and acetic acid–induced writhing as models for acute inflammation and pain, respectively, and showed that both responses are completely absent in IP-deficient mice. This study clearly demonstrated that PGI2, acting on the IP, works as a physiological mediator of these responses. However, it remains to be seen whether PGI2 and the IP play important roles in other types of inflammation and pain. The profiles of prostanoids generated in an inflammatory site change during the course of inflammation and are also dependent on the stimulus and site of inflammation (6). In pain, PGs are involved not only in hyperalgesia, an increased sensitivity to a painful stimulus, but also in allodynia, a pain response to a usually nonpainful stimulus. The latter condition is frequently seen in neuropathic pain and is thought to occur in the spinal cord, while the former is caused by sensitizing the free end of pain neurons in peripheral inflammation. It is interesting that the primary sensory neurons in the dorsal root ganglion express several types of prostanoid receptor mRNAs, including IP, EP1, EP3, and EP4 (2). The contribution of receptors other than IP to pain generation has not been determined.