Abstract
Pontine noradrenergic neurones form part of a descending inhibitory system that influences spinal nociceptive processing. Weak or absent descending inhibition is a common feature of chronic pain patients. We examined the extent to which the descending noradrenergic system is tonically active, how control of spinal neuronal excitability is integrated into thalamic relays within sensory-discriminative projection pathways, and how this inhibitory control is altered after nerve injury. In vivo electrophysiology was performed in anaesthetised spinal nerve-ligated (SNL) and sham-operated rats to record from wide dynamic range neurones in the ventral posterolateral thalamus (VPL). In sham rats, spinal block of α2-adrenoceptors with atipamezole resulted in enhanced stimulus-evoked and spontaneous firing in the VPL, and produced conditioned place avoidance. However, in SNL rats, these conditioned avoidance behaviours were absent. Furthermore, inhibitory control of evoked neuronal responses was lost, but spinal atipamezole markedly increased spontaneous firing. Augmenting spinal noradrenergic tone in neuropathic rats with reboxetine, a selective noradrenergic reuptake inhibitor, modestly reinstated inhibitory control of evoked responses in the VPL but had no effect on spontaneous firing. By contrast, clonidine, an α2 agonist, inhibited both evoked and spontaneous firing, and exhibited increased potency in SNL rats compared with sham controls. These data suggest descending noradrenergic inhibitory pathways are tonically active in sham rats. Moreover, in neuropathic states, descending inhibitory control is diminished, but not completely absent, and distinguishes between spontaneous and evoked neuronal activity. These observations may have implications for how analgesics targeting the noradrenergic system provide relief.
Highlights
Spinal a2-adrenoceptor inhibition has no effect on stimulus-evoked withdrawal responses in sham and spinal nerve–ligated rats
We describe how descending noradrenergic inhibition of spinal excitability impacts sensory coding in the ventral posterior thalamus
This distinction in inhibitory control has consequences for the actions of analgesics targeted at enhancing endogenous inhibitory tone in neuropathic conditions
Summary
Monoamine reuptake inhibitors are one of the commonly prescribed treatments for neuropathic pain, yet across different etiologies number needed to treat values only average around 6.4.17 Chronic pain conditions are frequently associated with a loss of endogenous inhibition,[68] and clearly, enhancement of noradrenergic tone can be an effective treatment.[17,79] Importantly, dividing patients into strata based on symptoms, which may reflect distinct underlying pathophysiological mechanisms, could improve patient outcomes.[13,60,79]. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. A Department of Neuroscience, Physiology & Pharmacology, University College London, London, United Kingdom, b Department of Pharmacology, University of Arizona, Tucson, AZ, United States
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