Plasticity of Endogenous Pain Modulatory Circuits in Neuropathy

Acute pain has a physiological role to protect against tissue damage. However, chronic pain can persist as a sequela of a multitude of diseases leading to maladaptive plasticity in the peripheral and central nervous system. Neuropathic syndromes are characterised by a complex combination of positive and negative sensory phenomena, which are often confounded by co-morbidities such as depression, anxiety and sleep disturbances having a devastating impact on quality of life. Meta-analyses suggest that pain with neuropathic characteristics has a prevalence of 7–10% in the general population and that large numbers of neuropathic patients fail to achieve adequate relief from all currently available treatments.

Early seminal studies demonstrated that brainstem nuclei can exert powerful modulation of nociceptive processing at the spinal level. It was later shown that this bi-directional control serves to amplify or suppress sensory transmission depending on context, expectation and emotional state. However, dysregulation of these pathways can contribute to pain pathophysiology. Neuropathic pain patients are frequently prescribed drugs (e.g. serotonin-noradrenaline reuptake inhibitors (SNRIs)) that target these predominantly monoaminergic pathways, but it is evident that when treated as a homogenous patient population many fail to manage their pain.

There is an extensive body of pre-clinical evidence that links altered descending control to the development and maintenance of chronic pain states, and these findings are supported by clinical studies based on imaging or psychophysical tests. In patients this is frequently studied using conditioned pain modulation (CPM), also referred to as diffuse noxious inhibitory controls, which may represent a translatable endpoint linking pre-clinical and clinical investigations. This form of quantitative sensory testing is based on the premise that ‘pain inhibits pain’ and likely represents a surrogate measure of the net balance of facilitatory and inhibitory signalling. Inefficient CPM provides an insight into pathophysiological mechanisms and has been observed in many chronic pain conditions. It is also linked to ‘pain vulnerability’ and could be useful for mechanism-led treatment selection by predicting analgesic responses to SNRIs.

There is still much to be determined about the signalling systems and precise circuitry that mediate top-down processing of pain transmission. The purpose of this Research Topic is to collect original research studies, as well as review and perspective articles, that provide recent advances in the understanding of endogenous pain modulation. We welcome pre-clinical and clinical manuscripts that cover, but are not restricted to, the following areas:

•- Neurophysiological or in vivo calcium imaging studies of neuronal activity.

•- Dissection of circuits using cutting-edge technologies.

•- Novel insights into mechanisms of drug action.

•- Clinical studies of descending pain modulatory networks.