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

2019

Eur J of Neuroscience

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Diffuse noxious inhibitory controls (DNIC) are a mechanism of endogenous descending pain modulation and are deficient in a large proportion of chronic pain patients. However, the pathways involved remain only partially determined with several cortical and brainstem structures implicated. This study examined the role of the dorsal reticular nucleus (DRt) and infralimbic (ILC) region of the medial prefrontal cortex in DNIC. In vivo electrophysiology was performed to record from dorsal horn lamina V/VI wide dynamic range neurones with left hind paw receptive fields in anaesthetised sham‐operated and L5/L6 spinal nerve‐ligated (SNL) rats. Evoked neuronal responses were quantified in the presence and absence of a conditioning stimulus (left ear clamp). In sham rats, DNIC were reproducibly recruited by a heterotopically applied conditioning stimulus, an effect that was absent in neuropathic rats. Intra‐DRt naloxone had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. In addition, intra‐DRt naloxone blocked DNIC in sham rats, but had no effect in SNL rats. Intra‐ILC lidocaine had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. However, differential effects were observed in relation to the expression of DNIC; intra‐ILC lidocaine blocked activation of DNIC in sham rats but restored DNIC in SNL rats. These data suggest that the ILC is not directly involved in mediating DNIC but can modulate its activation and that DRt involvement in DNIC requires opioidergic signalling.

Section: Methodssupporting

confidence: 81%

A study of cortical and brainstem mechanisms of diffuse noxious inhibitory controls in anaesthetised normal and neuropathic rats

Patel

2019

Eur J of Neuroscience

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“…Spontaneous activity in the VPL was inhibited also. Intraplantar injection of the active metabolite licarbazepine replicated the effects of systemic oxcarbazepine [31]. The data strongly support the concept that ongoing activity in primary afferent fibers drives spontaneous thalamic firing after spinal nerve injury and that oxcarbazepine produces a peripheral modality-selective inhibitory effect on sensory neuronal processing.…”

Section: Supraspinal Sites Of Action: Pain Modulationsupporting

confidence: 67%

Central Nervous System Targets: Supraspinal Mechanisms of Analgesia

Bannister

2020

Neurotherapeutics

While the acute sensation of pain is protective, signaling the presence of actual or potential bodily harm, its persistence is unpleasant. When pain becomes chronic, it has limited evolutionarily advantage. Despite the differing nature of acute and chronic pain, a common theme is that sufferers seek pain relief. The possibility to medicate pain types as varied as a toothache or postsurgical pain reflects the diverse range of mechanism(s) by which pain-relieving “analgesic” therapies may reduce, eliminate, or prevent pain. Systemic application of an analgesic able to cross the blood–brain barrier can result in pain modulation via interaction with targets at different sites in the central nervous system. A so-called supraspinal mechanism of action indicates manipulation of a brain-defined circuitry. Pre-clinical studies demonstrate that, according to the brain circuitry targeted, varying therapeutic pain-relieving effects may be observed that relate to an impact on, for example, sensory and/or affective qualities of pain. In many cases, this translates to the clinic. Regardless of the brain circuitry manipulated, modulation of brain processing often directly impacts multiple aspects of nociceptive transmission, including spinal neuronal signaling. Consideration of supraspinal mechanisms of analgesia and ensuing pain relief must take into account nonbrain-mediated effects; therefore, in this review, the supraspinally mediated analgesic actions of opioidergic, anti-convulsant, and anti-depressant drugs are discussed. The persistence of poor treatment outcomes and/or side effect profiles of currently used analgesics highlight the need for the development of novel therapeutics or more precise use of available agents. Fully uncovering the complex biology of nociception, as well as currently used analgesic mechanism(s) and site(s) of action, will expedite this process.

“…Baron and colleagues describe three sensory phenotypes (‘mechanical’, ‘thermal’ and ‘sensory loss’) in neuropathic patients ( Baron et al, 2017 ), though it is unclear whether inefficient CPM correlates with any of these. The sensory profile of the SNL model shares features with the ‘mechanical’ and ‘thermal’ phenotypes ( Dickenson and Patel, 2018 ; Patel et al, 2018a ), and diffuse noxious inhibitory controls are absent in this model ( Bannister et al, 2015 ). Speculatively, based on the modality and intensity dependent roles, enhanced descending facilitation terminating on 5-HT 2A and 5-HT 3 receptors may be associated with sub-groups within the ‘mechanical’ and ‘thermal’ sensory phenotypes; our current observations could help shape translational pharmacological studies.…”

Section: Discussionmentioning

confidence: 88%

“…Aberrant spontaneous firing of VPL WDR neurones in SNL rats is dependent on ongoing peripheral and spinal activity ( Patel et al, 2018a ). Neither block of spinal 5-HT 2A nor 5-HT 3 receptors inhibited spontaneous firing in sham and SNL rats.…”

Section: Discussionmentioning

confidence: 99%

Modality selective roles of pro-nociceptive spinal 5-HT2A and 5-HT3 receptors in normal and neuropathic states

Patel

2018

Neuropharmacology

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Descending brainstem control of spinal nociceptive processing permits a dynamic and adaptive modulation of ascending sensory information. Chronic pain states are frequently associated with enhanced descending excitatory drive mediated predominantly through serotonergic neurones in the rostral ventromedial medulla. In this study, we examine the roles of spinal 5-HT2A and 5-HT3 receptors in modulating ascending sensory output in normal and neuropathic states. 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. In sham rats, block of spinal 5-HT3Rs with ondansetron revealed tonic facilitation of noxious punctate mechanical stimulation, whereas blocking 5-HT2ARs with ketanserin had minimal effect on neuronal responses to evoked stimuli. The inhibitory profiles of both drugs were altered in SNL rats; ondansetron additionally inhibited neuronal responses to lower intensity punctate mechanical stimuli and noxious heat evoked responses, whereas ketanserin inhibited innocuous and noxious evaporative cooling evoked responses. Neither drug had any effect on dynamic brush evoked responses nor on spontaneous firing rates in both sham and SNL rats. These data identify novel modality and intensity selective facilitatory roles of spinal 5-HT2A and 5-HT3 receptors on sensory neuronal processing within the spinothalamic-somatosensory cortical pathway.