The plasticity of descending controls in pain: translational probing

Abstract

Descending controls, comprising pathways that originate in midbrain and brainstem regions and project onto the spinal cord, have long been recognised as key links in the multiple neural networks that interact to produce the overall pain experience. There is clear evidence from preclinical and clinical studies that both peripheral and central sensitisation play important roles in determining the level of pain perceived. Much emphasis has been put on spinal cord mechanisms in central excitability, but it is now becoming clear that spinal hyperexcitability can be regulated by descending pathways from the brain that originate from predominantly noradrenergic and serotonergic systems. One pain can inhibit another. In this respect diffuse noxious inhibitory controls (DNIC) are a unique form of endogenous descending inhibitory pathway since they can be easily evoked and quantified in animals and man. The spinal pharmacology of pathways that subserve DNIC are complicated; in the normal situation these descending controls produce a final inhibitory effect through the actions of noradrenaline at spinal α -adrenoceptors, although serotonin, acting on facilitatory spinal 5-HT receptors, influences the final expression of DNIC also. These descending pathways are altered in neuropathy and the effects of excess serotonin may now become inhibitory through activation of spinal 5-HT receptors. Conditioned pain modulation (CPM) is the human counterpart of DNIC and requires a descending control also. Back and forward translational studies between DNIC and CPM, gauged between bench and bedside, are key for the development of analgesic therapies that exploit descending noradrenergic and serotonergic control pathways.

Pain Modulation: From Conditioned Pain Modulation to Placebo and Nocebo Effects in Experimental and Clinical Pain

“…Catecholamines like norepinephrine and epinephrine signal through the α2-adrenergic receptors (Vo & Drummond, 2016) concentrated in the spinal cord to produce an inhibitory effect. Neurons of the dorsal horn in the spinal cord are directly inhibited by serotonin (from serotoninergic neurons) which, through its action on facilitatory spinal 5-HT3 receptors, influences the expression of CPM (Bannister & Dickenson, 2017). Measures of monoamines in men before a prostate surgery, the levels of monoamines, particularly adrenergics, was correlated to the efficacy of CPM (Parent et al, 2015).…”

“…Pharmacological treatments engaging descending noradrenergic and serotonergic control pathways have shown some efficacy in the treatment of pain, demonstrating the importance of serotonin and norepinephrine in pain modulation (Bannister & Dickenson, 2017; Kirkpatrick et al, 2015). Antidepressants such as tricyclic antidepressants, serotonin–norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors are used for pain management in chronic pain conditions such as neuropathic pain, migraines, and fibromyalgia (Dharmshaktu, Tayal, & Kalra, 2012).…”

“…The perception of pain is the result of several endogenous pain inhibitory and facilitatory mechanisms that trigger pain at all levels of the central nervous system. Conditioned pain modulation (CPM) is one unique form of endogenous descending inhibitory pathway (Bannister & Dickenson, 2017; Willer, Le Bars, & De Broucker, 1990). The use of the CPM paradigm in scientific research for evaluating the inherent pain inhibition ability of individuals is highly relevant for understanding normal functioning and various disease states, including the development, persistency and treatment of chronic pain.…”

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

“…The human counterpart measure, now referred to as conditioned pain modulation (CPM), is considered to be the psychophysical outcome of activating DNIC, and has received renewed interest in recent years as a sensory testing tool. CPM/DNIC likely reflect the net balance between descending inhibitory and facilitatory signalling; hence, the study of DNIC in rodents represents a useful translatable measure linking pre‐clinical and clinical investigations (Bannister & Dickenson, ). Inefficient CPM might provide insight into underlying pathophysiological mechanisms, and disturbances have been reported in neuropathic pain, irritable bowel syndrome, cluster headache and fibromyalgia (Albusoda et al., ; Kosek & Hansson, ; Perrotta et al., ; Yarnitsky, Granot, & Granovsky, ).…”

Functional connectivity of music-induced analgesia in fibromyalgia

“…The higher rs-FC between the THA and the PAG may relate to the neuronal facilitation of pain input into the central nervous system (Staud, 2012; Truini et al, 2016; Potvin & Marchand, 2016). Previous studies have found several brain regions such as the PAG, INS, FP, AMYG, hypothalamus, and RVM, are involved in the descending pain modulatory system (DPMS) (Tracey et al, 2007; Henderson & Keay, 2017; Chen et al, 2017; Bannister & Dickenson, 2017). Thus, a higher rs-FC between the brain stem and the THA may support the hypothesized facilitation of pain perception, though functional connectivity does not convey directionality or the type of neuronal function involved (excitation or inhibition) (Rogers et al, 2007; Vattikonda et al, 2016).…”