Autophagy: An Emerging Target for Developing Effective Analgesics

Abstract

Inadequate treatment of acute and chronic pain causes depression, anxiety, sleep disturbances, and increased mortality. Abuse and overdose of opioids and the side effects associated with chronic use of NSAID illustrate the need for development of safer and effective pain medication. Working toward this end, an in silico tool based on an emergent intelligence analytical platform that examines interactions between protein networks was used to identify molecular mechanisms involved in regulating the body's response to painful stimuli and drug treatments. Examining interactions between protein networks associated with the expression of over 20 different pain types suggests that the regulation of autophagy plays a central role in modulation of pain symptoms (see Materials and Methods). Using the topology of this regulatory scheme as an in silico screening tool, we identified that combinations of functions targeted by cannabidiol, myo-inositol, and fish oils with varying ratios of eicosapentaenoic and docosahexaenoic acids are projected to produce superior analgesia. For validating this prediction, we administered combinations of cannabidiol, myo-inositol, and fish oils to rats that received formalin injections in hind paws, prior to substance administration, and showed that analgesic effects produced by these combinations were comparable or superior to known NSAID analgesics, which suggests that these combinations have potential in treatment of pain.

Nutraceutical combination ameliorates imiquimod‐induced psoriasis in mice

“…Traditional medicines including vitamins, vegetable/animal oils, and treatments obtained from plants and animals have been used as therapeutic agents for the treatment of psoriasis (Raut & Wairkar, 2018). Our previous study, we evaluated the efficacy of krill oil, cannabidiol, and myo-inositol to alleviate formalin-induced inflammatory pain, and found that the combinations of cannabidiol and myo-inositol potentiated the efficacy of krill oil (Manivasakam et al, 2023). This study also evaluated the antipsoriatic effects of krill oil-containing combinations using an IMQ-induced psoriasis mice model and found strong evidence supporting their use as an antipsoriatic agent.…”

Autophagy may protect the brain against prolonged consequences of headache attacks: A narrative/hypothesis review

“…67,71,72,[121][122][123][124] Recent animal-based and in silico experiments suggest the regulation of autophagy plays a central role in the modulation of pain symptoms. 12 That role is mainly supported by the anti-inflammatory action of autophagy. Mechanistically, BDNF, P2X4R, and P2X7R are linked by ATP as it activates both receptors and mediates the release of BDNF from microglia in migraine.…”

“…Functionally, this association may be underlined by several effects, but neuroinflammation is the most consistently reported link 67,71,72,121–124 . Recent animal‐based and in silico experiments suggest the regulation of autophagy plays a central role in the modulation of pain symptoms 12 . That role is mainly supported by the anti‐inflammatory action of autophagy.…”

“…Also, the involvement of autophagy in the brain in other CNS diseases raises many questions 11 . Some recent experimental and bioinformatic studies point to autophagy as a possible therapeutic target for developing analgesics 12 …”

“…11 Some recent experimental and bioinformatic studies point to autophagy as a possible therapeutic target for developing analgesics. 12 In this narrative/hypothesis review, we present basic mechanisms of autophagy and provide information on the potential connections of autophagy and migraine on the basis of the results of experimental studies performed in vitro. We also hypothesize that the interplay between microglial cells and neurons may be crucial for these connections.…”