Disruption of Spinal Noradrenergic Activation Delays Recovery of Acute Incision-Induced Hypersensitivity and Increases Spinal Glial Activation in the Rat

Abstract

Clinical studies suggest that descending inhibitory controls from the brainstem are important for speeding recovery from pain following surgery. We examined the effects of destroying spinally projecting noradrenergic neurons via intrathecally administered antibody to dopamine β-hydroxylase conjugated to saporin (DβH-saporin) on recovery in an acute incisional pain model. Mechanical and thermal paw withdrawal thresholds and non-evoked spontaneous guarding scores were tested for several weeks postoperatively and analyzed using mixed effects growth curve modeling. DβH-saporin treatment resulted in a significant prolongation in the duration of mechanical and to a lesser degree thermal hypersensitivity in the ipsilateral paw of incised rats but did not increase the duration of spontaneous guarding. DβH-saporin treatment was also associated with increased microglial and astrocyte activation in the ipsilateral spinal cord 21 days postincision compared to IgG-saporin treated controls. Chronic intrathecal administration of the α2 adrenergic receptor antagonist atipamezole (50-200 μg/day) produced similar effects. These data suggest that spinally projecting noradrenergic pathways and spinal α2 adrenergic receptor activation are important for speeding recovery from hypersensitivity following surgical incision possibly by reducing spinal glial activation. Interventions that augment the noradrenergic system may be important to speed recovery from pain after surgery.Perspective-Endogenous descending spinal noradrenergic activation promotes resolution of incision induced hypersensitivity and inhibits spinal microglial and astrocyte activation in part through α2 adrenergic receptors.

Functional dichotomy in spinal- vs prefrontal-projecting locus coeruleus modules splits descending noradrenergic analgesia from ascending aversion and anxiety in rats

“…This mirrors their anatomical segregation ( Li et al, 2016 ) and implies that the modules could be capable of independent action, with recruitment in different behavioural contexts. We speculate that it may be the balance between recruitment of the ‘restorative’ LC :SC limb versus the ‘alarmist’ LC :PFC projection that determines whether pain following an injury resolves or persists into chronic pain (see also [ Arora et al, 2016 ; Brightwell and Taylor, 2009 ; Taylor and Westlund, 2017 ]). Further the recruitment of either module may actually reciprocally inhibit the other given the a 2-adrenoceptor-mediated feedback inhibition within the locus coeruleus ( Aghajanian et al, 1977 ).…”

The plasticity of descending controls in pain: translational probing

“…Importantly active noradrenergic mechanisms at the spinal cord level speed the recovery from hypersensitivity of rodents following a surgical incision (Arora et al . ).…”

“…; Arora et al . ). This particular inhibitory control was proposed to derive from the subnucleus reticularis dorsalis (SRD) (Bouhassira et al .…”

Engagement of spinal- vs prefrontal-projecting locus coeruleus neurons parses analgesia from aversion & anxiety in rats

“…This mirrors their anatomical segregation (Li et al, 2016) and implies that the modules could be capable of independent action, with recruitment in different behavioural contexts. We speculate that it may be the balance between recruitment of the 'restorative' LC :SC limb versus the 'alarmist' LC :PFC projection that determines whether pain following an injury resolves or persists into chronic pain (see also (Arora et al, 2016, Brightwell and Taylor, 2009, Taylor and Westlund, 2017). Further the recruitment of either module may actually reciprocally inhibit the other given the a2-adrenoceptor-mediated feedback inhibition within the locus coeruleus (Aghajanian et al, 1977).…”