Endothelin-1 (ET-1) is a newly described pain mediator that is involved in the pathogenesis of pain states ranging from trauma to cancer. ET-1 is synthesized by keratinocytes in normal skin and is locally released after cutaneous injury. While it is able to trigger pain through its actions on endothelin-A (ET(A)) receptors of local nociceptors, it can coincidentally produce analgesia through endothelin-B (ET(B)) receptors. Here we map a new endogenous analgesic circuit, in which ET(B) receptor activation induces the release of beta-endorphin from keratinocytes and the activation of G-protein-coupled inwardly rectifying potassium channels (GIRKs, also named Kir-3) linked to opioid receptors on nociceptors. These results indicate the existence of an intrinsic feedback mechanism to control peripheral pain in skin, and establish keratinocytes as an ET(B) receptor-operated opioid pool.

Isoflurane-nitrous oxide anesthesia is associated with a persistent deficit in RAM performance that is not explained by impaired locomotion. This impairment occurs in adult and aged rats, indicating that it is not an age-specific phenomenon. Thus, RAM performance is altered after general anesthesia for longer than predicted by the pharmacology of the drugs used, which, by inference, suggests a long-term deficit in learning/memory.

This study demonstrates that general anesthesia with isoflurane and nitrous oxide improves spatial memory in young rats but impairs it in aged rats for at least 3 wk, indicating that it can influence memory for much longer than previously recognized and may adversely affect memory processes in the aged.

Aged rats are impaired on a spatial memory task for at least 24-48 h after isoflurane-nitrous oxide anesthesia. In this study, we tested how long the impairment lasts and investigated the role of nitrous oxide. Eighteen-month-old rats were randomized to anesthesia for 2 h with 1.2% isoflurane with or without 70% nitrous oxide or a control group (30% oxygen). Two weeks later, rats were tested daily for 14 days on a 12-arm radial maze. The number of correct choices to first error, total errors, and time to complete the maze were recorded. Rats anesthetized with 1.2% isoflurane with 70% nitrous oxide made fewer correct choices before first error (P < or = 0.05). Trends toward similar results were noted for error rate and time to complete the maze, but these did not achieve statistical significance. Post hoc analysis comparing all anesthetized rats to controls demonstrated that anesthetized rats made fewer correct choices to first error (P < or = 0.05) and took longer to complete the maze (P