Elucidation of Mechanism of Pain Transmission by Gene Targeting

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Prolonged inflammation and nerve injury often lead to chronic pain such that noxious stimuli evoke hyperalgesia and innocuous tactile stimuli evoke pain (allodynia). With the advent of molecular biology, substance P and glutamate have been shown to be involved in acute pain and hyperalgesia, but a factor(s) involving allodynia had remained to be known. We found that intrathecal administration of prostaglandin E_2 induced allodynia in conscious mice and established an in vivo allodynia model. These several years, we have pharmacologically elucidated the mechanism of allodynia by use of receptor agonists and antagonists. Here, we applied this model to mice lacking lipocalin-type PGD synthase (L-PGDS) and obtained following results.While hyperalgesia induced by PGD_2 and PGE_2 was observed in L-PGDS-/- mice as well as wild-type mice, PGE_2-induced allodynia was not observed in L-PGDS-/-. Simultaneous administration of a femtogram amount of PGD_2 with PGE_2 induced allodynia in L-PGDS-/- m … More ice to the same extent as in wild-type mice. These results demonstrate that POD_2 is essential for induction of PGE_2-induced allodynia. Because PGD_2 blocked PGE_2-induced allodynia at a pg level, these experiments with PGDS-/- knockout mice first demonstrate that PGD_2 may regulate the induction of PGE_2-induced allodynia biphasically. Furthermore, the inhibitory amino acid GABA was suggested to mediate the action of PGD_2. At present experiments with knockout mice lacking other PG synthases and PG receptors are under investigation. Until recently, it was generally accepted that PGs act on pain transmission in the periphery and that opioids act, in the central nervous system. With the aid of developmental technology and genetargeting techniques, we have shown that both POs and opioids play important roles in induction of allodynia at the molecular level. We have recently succeeded in isolation of a novel peptide nocistatin from the brain and the cloning and characterization of its receptor are in progress. Less