Central Nervous System Targets: Supraspinal Mechanisms of Analgesia

Abstract

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.

A candidate neuroimaging biomarker for detection of neurotransmission-related functional alterations and prediction of pharmacological analgesic response in chronic pain

“…This was surprising for several reasons. First, the opioid system has a well-established role in pain regulation 53 , 54 and the dopamine system has equally been suggested to be involved in the supraspinal modulation of pain. 55 , 56 Second, alterations in opioid and dopaminergic neurotransmission in chronic pain have been reported in human PET studies.…”

Electroacupuncture Ameliorates Chronic Inflammatory Pain-Related Anxiety by Activating PV Interneurons in the Anterior Cingulate Cortex

“…Activity of ACC neurons is necessary and sufficient for the coding and processing of pain and the accompanying emotional pain, and the balance between neural excitation and inhibition is necessary for the normal function of the ACC ( Gong et al, 2010 ; Zugaib et al, 2014 ). In chronic pain clinical practice and basic research, changes in neurotransmitters in the central system have been found, which was caused by the dysregulation of GABAergic, glutamatergic, dopaminergic and opioidergic mechanisms ( Mhalla et al, 2010 ; Bannister and Dickenson, 2020 ; Yang et al, 2020 ). Dysfunction of GABAergic interneurons, as a major inhibitory system in the central nervous system, was reported to be closely related to the pathogenesis of anxiety-like behavior and chronic pain ( Möhler, 2012 ; Lau and Vaughan, 2014 ).…”

A candidate neuroimaging biomarker for detection of neurotransmission-related functional alterations and prediction of pharmacological analgesic response in chronic pain

“…This was surprising for several reasons. First, the opioid system has a well-established role in pain regulation (35,36) and the dopamine system has equally been suggested to be involved in the supraspinal modulation of pain (37,38). Second, alterations in opioid and dopaminergic neurotransmission in chronic pain have been reported in human PET studies (39,40).…”