Hopes for the Future of Pain Control

Abstract

Here we aim to present an accessible review of the pharmacological targets for pain management, and succinctly discuss the newest trends in pain therapy. A key task for current pain pharmacotherapy is the identification of receptors and channels orchestrating nociception. Notwithstanding peripheral alterations in the receptors and channels following pathophysiological events, the modulatory mechanisms in the central nervous system are also fundamental to the regulation of pain perception. Bridging preclinical and clinical studies of peripheral and central components of pain modulation, we present the different types of pain and relate these to pharmacological interventions. We firstly highlight the roles of several peripheral nociceptors, such as NGF, CGRP, sodium channels, and TRP-family channels that may become novel targets for therapies. In the central nervous system, the roles of calcium channels and gabapentinoids as well as NMDA receptors in generating excitability are covered including ideas on central sensitization. We then turn to central modulatory systems and discuss opioids and monoamines. We aim to explain the importance of central sensitization and the dialogue of the spinal circuits with the brain descending modulatory controls before discussing a mechanism-based effectiveness of antidepressants in pain therapy and their potential to modulate the descending controls. Emphasizing the roles of conditioned pain modulation and its animal’s equivalent, diffuse noxious inhibitory controls, we discuss these unique descending modulations as a potential tool for understanding mechanisms in patients suffering from pain. Mechanism-based therapy is the key to picking the correct treatments and recent clinical studies using sensory symptoms of patients as surrogates for underlying mechanisms can be used to subgroup patients and reveal actions of drugs that may be lost when studying heterogenous groups of patients. Key advances in the understanding of basic pain principles will impact our thinking about therapy targets. The complexity of pain syndromes will require tailored pharmacological drugs, often in combination or through drugs with more than one action, and often psychotherapy, to fully control pain.

Attenuation of the Diffuse Noxious Inhibitory Controls in Chronic Joint Inflammatory Pain Is Accompanied by Anxiodepressive-Like Behaviors and Impairment of the Descending Noradrenergic Modulation

“…In the monoarthritic rats, the DNIC were present ipsilaterally at the three time points assessed, namely at early (seven days), intermediate (28 days), and prolonged (42 days) time points. This corroborates other studies indicating that DNIC events are active in chronic pain states [20,23,[31][32][33]. DNIC were previously found in the carrageenan model of acute monoarthritis [31], in the CFA-induced monoarthritis model [20], and in the monoiodoacetate-induced osteoarthritis [19], a model of joint pain with a neuropathic component at the later stages [24,25,34].…”

Pharmacological interaction between NSAIDS with clomipramine and risperidone in mice visceral pain

“…Nociception is a complex condition controlled by diverse neuromodulators including the monoaminergic systems noradrenaline (NA), 5‐hydroxytryptamine 5‐HT), and dopamine (DA) have diverse modulatory roles in pain signaling. (Bannister & Dickenson, ; Bannister, Kucharczyk, & Dickenson, ; Cortes‐Altamirano et al, ). Therefore, the possibility of drugs that modify the monoaminergic system, such as clomipramine or risperidone, could enhance antinociception activity of NSAIDs.…”

Unaltered low nerve growth factor and high brain-derived neurotrophic factor levels in plasma from patients with fibromyalgia after a 15-week progressive resistance exercise

“…NGF is a key molecule for the sensitization of primary nociceptors associated with tissue inflammation and it is increased in inflamed tissue (8). Preclinical data have revealed that neutralization of endogenous NGF prevents inflammatory hyperalgesia (8).…”