Paracetamol sharpens reflection and spatial memory: a double-blind randomized controlled study in healthy volunteers

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Paracetamol sharpens reflection and spatial memory: a double-blind randomized controlled study in healthy volunteers

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Author(s): Gisèle Pickering ¹ ^, ² ^, ³ , Nicolas Macian ¹ ^, ² , Claude Dubray ¹ ^, ² ^, ³ , Bruno Pereira ⁴

Publication date (Electronic): 05 December 2016

Journal: Drug Design, Development and Therapy

Publisher: Dove Medical Press

Keywords: paracetamol, cognition, spatial memory, decision making, analgesia, therapeutic dose

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Abstract

Background

Acetaminophen (APAP, paracetamol) mechanism for analgesic and antipyretic outcomes has been largely addressed, but APAP action on cognitive function has not been studied in humans. Animal studies have suggested an improved cognitive performance but the link with analgesic and antipyretic modes of action is incomplete. This study aims at exploring cognitive tests in healthy volunteers in the context of antinociception and temperature regulation. A double-blind randomized controlled study (NCT01390467) was carried out from May 30, 2011 to July 12, 2011.

Methods

Forty healthy volunteers were included and analyzed. Nociceptive thresholds, core temperature (body temperature), and a battery of cognitive tests were recorded before and after oral APAP (2 g) or placebo: Information sampling task for predecisional processing, Stockings of Cambridge for spatial memory, reaction time, delayed matching of sample, and pattern recognition memory tests. Analysis of variance for repeated measures adapted to crossover design was performed and a two-tailed type I error was fixed at 5%.

Results

APAP improved information sampling task (diminution of the number of errors, latency to open boxes, and increased number of opened boxes; all P<0.05). Spatial planning and working memory initial thinking time were decreased ( P=0.04). All other tests were not modified by APAP. APAP had an antinociceptive effect ( P<0.01) and body temperature did not change.

Conclusion

This study shows for the first time that APAP sharpens decision making and planning strategy in healthy volunteers and that cognitive performance and antinociception are independent of APAP effect on thermogenesis. We suggest that cognitive performance mirrors the analgesic rather than thermic cascade of events, with possibly a central role for serotonergic and cannabinoid systems that need to be explored further in the context of pain and cognition.

Most cited references 45

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COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression.

N Chandrasekharan, Hu Dai, K. Roos … (2002)

Two cyclooxygenase isozymes, COX-1 and -2, are known to catalyze the rate-limiting step of prostaglandin synthesis and are the targets of nonsteroidal antiinflammatory drugs. Here we describe a third distinct COX isozyme, COX-3, as well as two smaller COX-1-derived proteins (partial COX-1 or PCOX-1 proteins). COX-3 and one of the PCOX-1 proteins (PCOX-1a) are made from the COX-1 gene but retain intron 1 in their mRNAs. PCOX-1 proteins additionally contain an in-frame deletion of exons 5-8 of the COX-1 mRNA. COX-3 and PCOX mRNAs are expressed in canine cerebral cortex and in lesser amounts in other tissues analyzed. In human, COX-3 mRNA is expressed as an approximately 5.2-kb transcript and is most abundant in cerebral cortex and heart. Intron 1 is conserved in length and in sequence in mammalian COX-1 genes. This intron contains an ORF that introduces an insertion of 30-34 aa, depending on the mammalian species, into the hydrophobic signal peptide that directs COX-1 into the lumen of the endoplasmic reticulum and nuclear envelope. COX-3 and PCOX-1a are expressed efficiently in insect cells as membrane-bound proteins. The signal peptide is not cleaved from either protein and both proteins are glycosylated. COX-3, but not PCOX-1a, possesses glycosylation-dependent cyclooxygenase activity. Comparison of canine COX-3 activity with murine COX-1 and -2 demonstrates that this enzyme is selectively inhibited by analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone, and is potently inhibited by some nonsteroidal antiinflammatory drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.

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Intention, action planning, and decision making in parietal-frontal circuits.

Richard Andersen, He Cui (2009)

The posterior parietal cortex and frontal cortical areas to which it connects are responsible for sensorimotor transformations. This review covers new research on four components of this transformation process: planning, decision making, forward state estimation, and relative-coordinate representations. These sensorimotor functions can be harnessed for neural prosthetic operations by decoding intended goals (planning) and trajectories (forward state estimation) of movements as well as higher cortical functions related to decision making and potentially the coordination of multiple body parts (relative-coordinate representations).

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Acetaminophen reduces social pain: behavioral and neural evidence.

C. Nathan DeWall, Geoff MacDonald, Gregory Webster … (2010)

Pain, whether caused by physical injury or social rejection, is an inevitable part of life. These two types of pain-physical and social-may rely on some of the same behavioral and neural mechanisms that register pain-related affect. To the extent that these pain processes overlap, acetaminophen, a physical pain suppressant that acts through central (rather than peripheral) neural mechanisms, may also reduce behavioral and neural responses to social rejection. In two experiments, participants took acetaminophen or placebo daily for 3 weeks. Doses of acetaminophen reduced reports of social pain on a daily basis (Experiment 1). We used functional magnetic resonance imaging to measure participants' brain activity (Experiment 2), and found that acetaminophen reduced neural responses to social rejection in brain regions previously associated with distress caused by social pain and the affective component of physical pain (dorsal anterior cingulate cortex, anterior insula). Thus, acetaminophen reduces behavioral and neural responses associated with the pain of social rejection, demonstrating substantial overlap between social and physical pain.

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Author and article information

Journal

Journal ID (nlm-ta): Drug Des Devel Ther

Journal ID (iso-abbrev): Drug Des Devel Ther

Journal ID (publisher-id): Drug Design, Development and Therapy

Title: Drug Design, Development and Therapy

Publisher: Dove Medical Press

ISSN (Electronic): 1177-8881

Publication date Collection: 2016

Publication date (Electronic): 05 December 2016

Volume: 10

Pages: 3969-3976

Affiliations

[1 ]University Hospital, CHU Clermont-Ferrand, Centre de Pharmacologie Clinique

[2 ]Inserm, CIC 1405, UMR Neurodol 1107

[3 ]Clermont Université, Laboratoire de Pharmacologie, Faculté de médicine

[4 ]CHU de Clermont-Ferrand, Délégation Recherche Clinique Innovation, Clermont-Ferrand, France

Author notes

Correspondence: Gisèle Pickering, Faculty of Medicine, Clinical Pharmacology Centre, Bâtiment 3C, CHU of Clermont-Ferrand, 58 Montalembert Road, 63001 Clermont-Ferrand cedex, France, Tel +33 4 7317 8416, Fax +33 4 7317 8412, Email gisele.pickering@ 123456udamail.fr

Article

Publisher ID: dddt-10-3969

DOI: 10.2147/DDDT.S111590

PMC ID: 5147402

SO-VID: 062a21d4-7535-4db8-a167-2f8e6f6a221c

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The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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Paracetamol sharpens reflection and spatial memory: a double-blind randomized controlled study in healthy volunteers

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Abstract

Background

Methods

Results

Conclusion

Most cited references 45

COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression.

Intention, action planning, and decision making in parietal-frontal circuits.

Acetaminophen reduces social pain: behavioral and neural evidence.

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