Modulation of responses to inflammatory mediators of nociceptive neurons by repeated cold stress loading

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Specific alteration of rhythm in environmental temperature (SART) stress induces hyperalgesia. Prostaglandin (PG) E2 is a substance known to induce hyperalgesia both in the periphery and central nervous system. Our previous report showed that PG EP3 receptor (EP3R) agonist augmented the response of the polymodal receptor, a type of nociceptor, to bradykinin (BK), in vitro, using canine testis-spermatic nerve preparations. To obtain conclusive evidence that EP3R is involved in the sensitization of the response to BK, we cloned and sequenced EP3R cDNA from canine dorsal root ganglia (DRG). Two different cDNAs encoding the isoforms with different C-termini were obtained. EP3R agonist reduced forskolin-induced increase in cAMP in the cells stably expressing either of these variants, and this reduction was abolished by incubation with pertussis toxin, suggesting that the activation of the two isoforms of EP3R exerts an inhibitory effect on the forskolin-induced cAMP accumulation through Gi protein.Effects of SART stress were studied both in normal and in the adjuvant inflamed rats. BK sensitivity of nociceptors increases in adjuvant inflamed rats. The expression of B2 receptor (B2R) mRNA detected with RT-PCR also increased in rat DRG two weeks after inoculation of complete Freund's adjuvant. This result suggests that chronic inflammation increases BK sensitivity of nociceptors, in part with the up-regulation of BKB2R. During SART stress, the body weight of rats did not clearly increase and the mechanical pain threshold decreased. The expression of corticotrophin releasing hormone (CRH) mRNA tended to increase in the rat hypothalamus with SART stress. SART stress did not additionally decrease the mechanical pain threshold in inflamed rats. The hyperalgesia induced by chronic inflammation might have reached the maximum or some tolerance to inflammation might have been induced by CRH.