Evidence for suppression of spinal glial activation by dexmedetomidine in a rat model of monoarthritis

Abstract

SUMMARY1. Spinal glial cells play a key role in developing and maintaining allodynia and hyperalgesia following tissue inflammation. Dexmedetomidine, a highly selective a 2 -adrenoceptor (a 2 -AR) agonist, has exhibited a significant analgesic effect in various rodent models of chronic pain. However, whether spinal glial activation is involved in the analgesic effect of dexmedetomidine remains unknown. The present study investigated whether spinal administration of dexmedetomidine could antagonize glial activation in the spinal dorsal horn and attenuate thermal hyperalgesia in complete Freund's adjuvant (CFA)-induced ankle joint monoarthritic (MA) rats.2. Unilateral intra-articular injection of CFA produced a robust activation of microglia and astrocytes in the spinal cord, which was associated with the development and maintenance of thermal hyperalgesia. Repeated lumbar puncture (LP) administration of dexmedetomidine (10 lg) significantly attenuated MA-induced thermal hyperalgesia in a cumulative manner. Monoarthritis-induced spinal glial activation was also suppressed following dexmedetomidine application. The a 2A -AR, essential for the antinociceptive effects of a 2 -AR agonists, was detected in spinal neurons and glia, as well as in dorsal root ganglion primary afferent neurons, which may be implicated in dexmedetomidine-induced suppression of spinal glial activation and antihyperalgesic effects.3. These data provide the first evidence that blocking spinal glial activation is involved in the analgesic action of dexmedetomidine.

Individual Differences in Acute Pain-induced Endogenous Analgesia Predict Time to Resolution of Postoperative Pain in the Rat

“…44,45 We show that a reduction in spinal norepinephrine results in long term increases in spinal glial activation following peripheral nerve injury, similar to previous studies in our lab that examined earlier time points. 27 Consistent with our findings, noradrenergic receptor agonists have been shown to inhibit glial activation in vivo in rodent neuropathic pain models 46,47 and in vitro in spinal microglia 48 and astrocyte cultures 49 . Enhanced glial activation after injury likely results from increased primary afferent release of stimulating factors ( e.g.…”

Preventive and Alleviative Effect of Tramadol on Neuropathic Pain in Rats: Roles of α2-Adrenoceptors and Spinal Astrocytes

“…Recent findings suggest that astrocytes, but not microglia, express a 2A -ARs (50). Furthermore, dexmedetomidine, a highly selective a 2 -AR agonist, inhibits the activation of spinal astrocytes and extracellular signal-regulated kinase (ERK) signaling, but not that of microglia, probably by activating a 2 -AR expressed on astrocytes, which suppresses inflammatory and neuropathic pain (50,51). Taken together, it is suggested that the increase in NA induced by tramadol or amitriptyline acts on astrocytic a 2 -ARs and inhibits the pSNL-induced activation of spinal astrocytes, which may contribute to the preventive effect on neuropathic pain.…”

Involvement of Protein Kinase B/Akt in Analgesic Effect of Dexmedetomidine on Neuropathic Pain

“…Our previous study demonstrated that a 2A -AR was diffusely distributed in the primary afferents and dorsal horn neurons [5]; thus, presynaptic and postsynaptic a 2A -AR expressions in the spinal dorsal horn might both upregulate in CCI rats and contribute to dexmedetomidine-induced antiallodynia.…”