Figure 6.

Schematic illustration of the dynamic interaction between dynorphin and κ-opioid and NMDA receptors. (a) Normal state. Prodynorphin mRNA expression is at the physiological level. Dynorphin supply is sufficient only to activate κ-opioid receptors (opioid action). (b) Injury to the sciatic nerve. The level of prodynorphin mRNA is increased (as evidenced by the present study and literature data); therefore, more dynorphin is released and, apart from κ-opioid receptor activation (opiod action), the activation of NMDA receptors occurs (nonopioid action). As a result of this situation, the allodynia develops as a characteristic feature of neuropathic pain. (c) Injury to the sciatic nerve+administration of the κ-receptor antagonists norBNI or GNTI. The administration of κ-opioid antagonists blocks the opioid action of dynorphin and potentiates allodynia by a more potent activation of NMDA receptors by dynorphin. (d) Injury to the sciatic nerve+administration of the κ-receptor antagonists norBNI or GNTI+ketamine or DYN A/S. The effect described in (c) is antagonized by DYN A/S and by administration of ketamine, the NMDA receptor antagonist. These data explain that endogenous dynorphin is responsible for the abnormal pain sensations in neuropathic pain. Antagonists of the κ-opioid receptors worsen the situation because of potentiation of the nonopioid effects of dynorphin.