Activation of spinal dorsal horn astrocytes by noxious stimuli involves descending noradrenergic signaling

Abstract

Astrocytes are critical regulators of neuronal function in the central nervous system (CNS). We have previously shown that astrocytes in the spinal dorsal horn (SDH) have increased intracellular Ca2+ levels following intraplantar injection of the noxious irritant, formalin. However, the underlying mechanisms remain unknown. We investigated these mechanisms by focusing on the role of descending noradrenergic (NAergic) signaling because our recent study revealed the essential role of the astrocytic Ca2+ responses evoked by intraplantar capsaicin. Using in vivo SDH imaging, we found that the Ca2+ level increase in SDH astrocytes induced by intraplantar formalin injection was suppressed by ablation of SDH-projecting locus coeruleus (LC)-NAergic neurons. Furthermore, the formalin-induced Ca2+ response was dramatically decreased by the loss of α1A-adrenaline receptors (ARs) in astrocytes located in the superficial laminae of the SDH. Moreover, similar inhibition was observed in mice pretreated intrathecally with an α1A-AR-specific antagonist. Therefore, activation of α1A-ARs via descending LC-NAergic signals may be a common mechanism underlying astrocytic Ca2+ responses in the SDH evoked by noxious stimuli, including chemical irritants.

Spinally projecting noradrenergic neurons of the locus coeruleus display resistance to AAV2retro-mediated transduction

“…Recent studies have used a similar strategy to manipulate spinally-projecting noradrenergic neurons using AAV2retro serotype vectors, and reported efficient labelling of these neurons from the spinal cord. 11,21,22 One possible explanation for differences between these findings and the present study could be the promoter choice and subsequent expression of genetic material in noradrenergic neurons. To explore this possibility, we repeated our tracing studies with CTb and AAV2retro vectors containing a hSyn promoter instead of the CAG promoter used in the previous experiment.…”

“…Recently, similar strategies have been used to functionally manipulate descending LC neurons by injecting AAV2retro serotype vectors into the spinal cord. 11,21,22 In one study, AAV2retro.ESYN.cre was used to transduce projections to the spinal cord with cre, and bilateral injections into the LC with an AAV containing a cre-dependent hM3Dq were used to activate NA-containing LC neurons that project to the spinal cord. 11 This intersectional approach may be a more sensitive strategy, leading to a more efficient capture of the NA-containing neurons.…”

Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn

“…Therefore, nerve injury-induced plasticity in the spinal α2-adrenoceptors represents enhanced descending inhibition or sensitivity of the dorsal horn nociceptive neurons [ 49 , 50 ]. However, some studies show that activation of α1A-ARs via descending LC noradrenergic signals may be a common mechanism underlying astrocytic Ca 2+ responses in the SDH evoked by noxious stimuli [ 51 ]. Intrathecal NE induces mechanical pain hypersensitivity via α1A-ARs in astrocytes, and chemogenetic stimulation of SDH astrocytes is sufficient to produce the hypersensitivity [ 16 ].…”

Batatasin III, a Constituent of Dendrobium scabrilingue, Improves Murine Pain-like Behaviors with a Favorable CNS Safety Profile

“…Formalin challenge also modulates central immune cells by activating microglia and astrocytes in the spinal cord. The activation of microglia and astrocytes contributes to central sensitization, leading to enhanced pain transmission. ,− In the present study, the effects of batatasin III on pain-like behaviors in formalin-induced mice were assessed. As presented in Figure , the intraplantar injection of formalin promoted a robust increase in hind paw licking behaviors in phases I and II of the formalin model.…”