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

Abstract

Key pointsr Despite the clinical importance of pre-emptive analgesia, the mechanisms by which it attenuates pain associated with central sensitization are poorly understood.r We find that fentanyl and the α2-adrenoceptor agonist dexmedetomidine (Dex) differ significantly in their modulatory actions on noxious mechanical and noxious heat-evoked nociception in vivo.r Unlike fentanyl, Dex modified descending control of nociception by decreasing the threshold for descending inhibition and/or increasing the threshold for descending facilitation.r Dex exhibited after-actions on activities of thalamus in prolongation of noxious heat-evoked paw withdrawal latency that persisted for at least 7 days.r This study provides insight into the organization of thalamic modulation in pre-emptive analgesia.Abstract We investigated and compared the antinociceptive effects of intraperitoneal administration of fentanyl (2-60 μg kg −1 ) and dexmedetomidine (Dex, 1-10 μg kg −1 ; a highly selective α2-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 1-1.5 h (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 1-1.5 h period followed by a second, slowly developing increase in latency that persisted for at least 7 days (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 (α2-adrenoceptor antagonist) or WAY-100635 (5-HT 1A 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.

Influence of intrathecal injection with dexmedetomidine on the behavioral ability and analgesic effects on rats with neuropathic pain and expression of protein kinase C in the spinal dorsal horn

“…In the central nervous system, dexmedetomidine has an effect on the locus coeruleus nucleus and plays an important role in sedation and hypnosis via antagonism of the sympathetic nerve activity under the combined action of the central and peripheral neurotransmitters ( 12 ). A research study ( 13 ) has indicated that dexmedetomidine could inhibit the activity of the signal transduction pathway of the dorsal horn neurons, decrease Ca 2+ influx and reduce the release of neurotransmitters. Presently, dexmedetomidine is widely used in perioperative anesthesia and postoperative analgesia.…”

Incidence and risk factors of chronic pain following hysterectomy among Southern Jiangsu Chinese Women

“…It has been reported that dexmedetomidine decrease sympathetic tone and cytokines release to surgical stress [ 41 ], which could attenuate peripheral sensitization and central sensitization associated with long-term potentiation and CPSP. Furthermore, in an experimental study, dexmedetomidine modified descending control of nociception by decreasing the threshold for descending inhibition and/or increasing the threshold for descending facilitation [ 42 ]. These results may explain that our clinic practice with dexmedetomidine infusion with 0.5 μg/kg/h decrease the rate of development of CPSP after hysterectomy.…”

Effects of Intramuscular Heating-needle Stimulation in Controlling Adjuvant-induced Muscle Nociception in Rats: Differential Roles of Thalamic Purinergic P2X3 Receptors

“…Importantly, these earlier results revealed critical roles of the thalamic MD and VM nuclei in descending facilitatory and inhibitory control of noxious mechanically and heat-evoked nociception (You et al, 2013). In contrast to tonic modulation of proprioception and sympathetic activities during the physiological state, earlier studies further demonstrated that endogenous modulation of pain (facilitation and inhibition) is, however, inactive or relatively 'silent', if noxious stimulation is insufficient (You et al, 2010(You et al, , 2013(You et al, , 2014(You et al, , 2016. Moreover, peripheral C-fibre afferents were shown to have a key role in initiation of both endogenous inhibition and facilitation.…”