Pre-emptive analgesia and its supraspinal mechanisms: enhanced descending inhibition and decreased descending facilitation by dexmedetomidine

We investigated and compared the antinociceptive effects of intraperitoneal administration of fentanyl (2-60gkg(-1)) and dexmedetomidine (Dex, 1-10gkg(-1); a highly selective 2-adrenoceptor agonist) in the regulation of nociception assessed by measuring noxious paw withdrawal reflexes in rats. Fentanyl elevated noxious mechanical paw withdrawal threshold and prolonged paw withdrawal heat latency within 1-1.5h (P<0.05). Dex failed to affect the mechanical paw withdrawal threshold, yet significantly prolonged the paw withdrawal heat latency in a bi-phasic manner; a short transient 1-1.5h period followed by a second, slowly developing increase in latency that persisted for at least 7days (P<0.05). Lesion of the dorsolateral funiculus (DLF) did not influence fentanyl-induced antinociceptive effects, indicating peripheral and spinal antinociceptive mechanisms. By contrast, the Dex-induced second, but not the first, phase of the prolonged paw withdrawal heat latency was significantly blocked by the lesion of either DLF or thalamic ventromedial (VM) nuclei, and was attenuated by intracerebral administration of either atipamezole (2-adrenoceptor antagonist) or WAY-100635 (5-HT1A receptor antagonist) into the VM nuclei (P<0.05). Upon intramuscular 5.8% saline-induced muscle nociception, pre-emptive injection of fentanyl enhanced mechanical hyperalgesia and blocked heat hypoalgesia, whereas Dex significantly prevented the occurrence of mechanical hyperalgesia and enhanced heat hypoalgesia. It is suggested that Dex, but not fentanyl, significantly enhances descending inhibition and/or decreases descending facilitation to modulate pain and nociception. The present study provides novel insight into thalamus-mediated mechanisms in pre-emptive analgesia.