Analgesia without opioids

Abstract

P ain is one of the main reasons why people consult a doctor. Often, especially in North America, they walk away with an opioid prescription. But opioids are increasingly viewed as unsuited to managing chronic pain. "Opioids are unbelievably effective for shortterm pain relief, such as after operations, but for long-term pain they are less effective and come with a very considerable burden of side effects, " says Peter McNaughton, a pharmacologist at King's College London. Their use can lead to dependency, addiction and even death.

Peripherally targeted analgesia via AAV-mediated sensory neuron–specific inhibition of multiple pronociceptive sodium channels

“…PSN-restricted inhibition of multiple pronociceptive TTXs Na VS is predicted to have advantages for DRG-targeted analgesia, as a recent expert commentary states that excitability of neurons is determined by several different Na v channels, therefore targeting one alone may not be sufficient. They explain that this may correlate with the inadequate analgesic pharmaceutics that inhibit only Na v 1.7 ( 60 ). It is known that individuals and animal models that are heterozygous for null mutations of Na V 1.7 are normal in sensory phenotypes.…”

New botulinum neurotoxin constructs for treatment of chronic pain

“…Together, our study indicates that a precisely engineered el-iBoNT molecule may provide a new therapeutic option to chronic pain sufferers. This is of great importance considering that there are very limited therapeutic options currently available for chronic pain, and these often lack efficacy, bring about intolerable side effects, and fuel the opioid crisis ( King, 2019 ).…”

Ligand-Directed Labeling of the Adenosine A1 Receptor in Living Cells

“…The adenosine A 1 AR receptor is a subtype of the four adenosine receptors, a class of GPCRs that are activated by the endogenous purine nucleoside adenosine. , Modulation of the A 1 AR pharmacology provides therapeutic opportunities for chronic and acute disease conditions, including cardiovascular and respiratory diseases, central nervous system (CNS) disorders, and inflammatory diseases such as cancer and neuropathic pain . Recent studies have shown that targeting A 1 AR signaling through allosteric modulators and biased agonists could represent a promising therapeutic strategy for treating chronic pain with nonopioid analgesic agents . However, despite their significant potential, the clinical translation of A 1 AR-targeting small molecules has suffered from a limited understanding of the function of A 1 AR and the mechanisms and differences that regulate the spatial (e.g., specific cellular localization and environment) and temporal (e.g., signaling duration) dynamics of its biology in living cells. , To address these problems, the development of a ligand-directed labeling approach for the permanent bioconjugation of the A 1 AR with a functional probe could provide a noninvasive approach for monitoring and studying receptor function and dynamics in its native health and disease conditions without genetic manipulation.…”

“… 13 Recent studies have shown that targeting A 1 AR signaling through allosteric modulators 14 and biased agonists 15 could represent a promising therapeutic strategy for treating chronic pain with nonopioid analgesic agents. 16 However, despite their significant potential, the clinical translation of A 1 AR-targeting small molecules has suffered from a limited understanding of the function of A 1 AR and the mechanisms and differences that regulate the spatial (e.g., specific cellular localization and environment) and temporal (e.g., signaling duration) dynamics of its biology in living cells. 13 , 17 To address these problems, the development of a ligand-directed labeling approach for the permanent bioconjugation of the A 1 AR with a functional probe could provide a noninvasive approach for monitoring and studying receptor function and dynamics in its native health and disease conditions without genetic manipulation.…”