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The Analgesic and Anxiolytic Effect of Souvenaid, a Novel Nutraceutical, Is Mediated by Alox15 Activity in the Prefrontal Cortex

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Abstract

Pain and anxiety have a complex relationship and pain is known to share neurobiological pathways and neurotransmitters with anxiety. Top-down modulatory pathways of pain have been shown to originate from cortical and subcortical regions, including the dorsolateral prefrontal cortex. In this study, a novel docosahexaenoic acid (DHA)-containing nutraceutical, Souvenaid, was administered to mice with infraorbital nerve ligation-induced neuropathic pain and behavioral responses recorded. Infraorbital nerve ligation resulted in increased face wash strokes of the face upon von Frey hair stimulation, indicating increased nociception. Part of this response involves general pain sensitization that is dependent on the CNS, since increased nociception was also found in the paws during the hot plate test. Mice receiving oral gavage of Souvenaid, a nutraceutical containing DHA; choline; and other cell membrane components, showed significantly reduced pain sensitization. The mechanism of Souvenaid’s activity involves supraspinal antinociception, originating in the prefrontal cortex, since inhibition of the DHA-metabolizing enzyme 15-lipoxygenase (Alox15) in the prefrontal cortex attenuated the antinociceptive effect of Souvenaid. Alox15 inhibition also modulated anxiety behavior associated with pain after infraorbital nerve ligation. The effects of Souvenaid components and Alox15 on reducing central sensitization of pain may be due to strengthening of a known supraspinal antinociceptive pathway from the prefrontal cortex to the periaqueductal gray. Together, results indicate the importance of the prefrontal cortex and DHA/Alox15 in central antinociceptive pathways and suggest that Souvenaid may be a novel therapeutic for neuropathic pain.

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Abbreviations

AA:

Arachidonic acid

AD:

Alzheimer ’s disease

Alox15:

Arachidonate 15-lipoxygenase

Alox15B:

Epidermis type 15-lipoxygenase

CNS:

Central nervous system

DHA:

Docosahexanoic acid

DMSO:

Dimethyl sulfoxide

fMRI:

Functional magnetic resonance imaging

FST:

Forced swim test

HFS:

High frequency stimulation

ION:

Infraorbital nerve

IONL:

Infraorbital nerve ligation

IL-1β:

Interleukin-1 beta

iPLA2 :

Calcium independent Phospholipase A2

NPD1:

Neuroprotectin D1

PAG:

Periaqueductal gray

PFC:

Prefrontal cortex

PLA2 :

Phospholipase A2

PUFA:

Polyunsaturated Fatty Acid

PVDF:

Polyvinylidene difluoride

RvD1:

Resolvin D1

RvD2:

Resolvin D2

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel

TBST:

Tris buffered saline–Tween

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Acknowledgments

This work was supported by grants from the National Medical Research Council and the National University Health System of Singapore.

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Authors and Affiliations

  1. Department of Anatomy, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, 119260, Singapore

    Suku-Maran Shalini & Wei-Yi Ong

  2. Neurobiology and Ageing Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore

    Suku-Maran Shalini & Wei-Yi Ong

  3. Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore, Singapore

    Deron R. Herr

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  1. Suku-Maran Shalini
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Shalini, SM., Herr, D.R. & Ong, WY. The Analgesic and Anxiolytic Effect of Souvenaid, a Novel Nutraceutical, Is Mediated by Alox15 Activity in the Prefrontal Cortex. Mol Neurobiol 54, 6032–6045 (2017). https://doi.org/10.1007/s12035-016-0138-2

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