Diffuse noxious inhibitory controls and nerve injury

Abstract

Diffuse noxious inhibitory controls (DNICs) utilize descending inhibitory controls through poorly understood brain stem pathways. The human counterpart, conditioned pain modulation, is reduced in patients with neuropathy aligned with animal data showing a loss of descending inhibitory noradrenaline controls together with a gain of 5-HT3 receptor-mediated facilitations after neuropathy. We investigated the pharmacological basis of DNIC and whether it can be restored after neuropathy. Deep dorsal horn neurons were activated by von Frey filaments applied to the hind paw, and DNIC was induced by a pinch applied to the ear in isoflurane-anaesthetized animals. Spinal nerve ligation was the model of neuropathy. Diffuse noxious inhibitory control was present in control rats but abolished after neuropathy. α2 adrenoceptor mechanisms underlie DNIC because the antagonists, yohimbine and atipamezole, markedly attenuated this descending inhibition. We restored DNIC in spinal nerve ligated animals by blocking 5-HT3 descending facilitations with the antagonist ondansetron or by enhancing norepinephrine modulation through the use of reboxetine (a norepinephrine reuptake inhibitor, NRI) or tapentadol (μ-opioid receptor agonist and NRI). Additionally, ondansetron enhanced DNIC in normal animals. Diffuse noxious inhibitory controls are reduced after peripheral nerve injury illustrating the central impact of neuropathy, leading to an imbalance in descending excitations and inhibitions. Underlying noradrenergic mechanisms explain the relationship between conditioned pain modulation and the use of tapentadol and duloxetine (a serotonin, NRI) in patients. We suggest that pharmacological strategies through manipulation of the monoamine system could be used to enhance DNIC in patients by blocking descending facilitations with ondansetron or enhancing norepinephrine inhibitions, so possibly reducing chronic pain.

Brain activity changes in a macaque model of oxaliplatin-induced neuropathic cold hypersensitivity

“…The pharmacological mechanism of duloxetine is blocking synaptic reuptake of serotonin and norepinephrine, increasing levels of these neurotransmitters, thereby reducing pain 34 . Whether this occurs directly, at SII/Ins 35–38 or indirectly through, for example, modulation of brainstem serotonin and norepinephrine neurons that project to cortical areas 39 , remains to be elucidated. A peripheral site of action could also play a role as duloxetine blocks peripheral nerve-expressed sodium channel function 40 .…”

Reticular Formation and Pain: The Past and the Future

“…Another evidence that pain facilitation likely opposes the effects of DNIC comes from a study showing that chronic treatment with morphine, which induces paradoxical opioid-induced hyperalgesia (Lee et al, 2011), was shown to eliminate DNIC by activating pain facilitatory neurons in the RVM (Okada-Ogawa et al, 2009). Additionally, several other recent studies show that descending spinal inhibitory noradrenergic pathways are necessary for the expression of DNIC (Bannister et al, 2015; Peters et al, 2015). Finally, DNIC is decreased in patients and animal models with chronic pain and studies using the rat show that pharmacologically increasing noradrenaline, which is deficient at the spinal cord during neuropathic pain (Hughes et al, 2013), as well as blocking serotoninergic descending facilitation mediated by 5-HT3 receptors, restores DNIC in neuropathic animals (Bannister et al, 2015).…”

“…Additionally, several other recent studies show that descending spinal inhibitory noradrenergic pathways are necessary for the expression of DNIC (Bannister et al, 2015; Peters et al, 2015). Finally, DNIC is decreased in patients and animal models with chronic pain and studies using the rat show that pharmacologically increasing noradrenaline, which is deficient at the spinal cord during neuropathic pain (Hughes et al, 2013), as well as blocking serotoninergic descending facilitation mediated by 5-HT3 receptors, restores DNIC in neuropathic animals (Bannister et al, 2015). Taking these recent findings into account and given the fact that chronic pain results from an imbalance between descending inhibition and facilitation with the imbalance towards increasing descending facilitation (Ossipov et al, 2014), assessing DNIC in patients could potentially constitute a relevant tool to monitor alterations in the endogenous pain modulatory pathways (van Wijk and Veldhuijzen, 2010), which could potentially help identify patients at risk for development of chronic pain and ultimately help find better pain treatments.…”

Neuropathy following spinal nerve injury shares features with the irritable nociceptor phenotype: A back‐translational study of oxcarbazepine

“…The homogeneity of animal models complicates the translation of pre-clinical findings to patient groups exhibiting heterogeneous symptoms. Sensory profiles may represent a surrogate for underlying mechanisms (Baron et al, 2017;Bouhassira & Attal, 2016;Truini, Garcia-Larrea, & Cruccu, 2013), and a mechanism-based approach would represent a progressive way to link animal and clinical research (for example see (Yarnitsky et al, 2012) and (Bannister, Patel, Goncalves, Townson, & Dickenson, 2015)). Attempts to correlate lidocaine sensitivity to sensory profiles have not always proved successful (Haroutounian et al, 2014), although patients with the irritable nociceptor phenotype were more likely to achieve relief from a 5% lidocaine patch against pain paroxysms and deep pain (Demant et al, 2015).…”