Spinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors, are involved in antinociception by systemically administered amitriptyline

Jean Liu; Allison R. Reid; Jana Sawynok

doi:10.1016/j.ejphar.2012.10.042

Spinal serotonin 5-HT₇ and adenosine A₁ receptors, as well as peripheral adenosine A₁ receptors, are involved in antinociception by systemically administered amitriptyline

Jean Liu, Allison R. Reid, Jana Sawynok

Medicine

Medicine

Research output: Contribution to journal › Article › peer-review

27 Citations (Scopus)

Abstract

The present study explored a link between spinal 5-HT₇ and adenosine A₁ receptors in antinociception by systemic amitriptyline in normal and adenosine A₁ receptor knock-out mice using the 2% formalin test. In normal mice, antinociception by systemic amitriptyline 3 mg/kg was blocked by intrathecal administration of the selective adenosine A ₁ receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) 10 nmol. Blockade was also seen in adenosine A₁ receptor +/+ mice, but not in -/- mice lacking these receptors. In both normal and adenosine A ₁ receptor +/+ mice, the selective 5-HT₇ receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl) ethyl]pyrrolidine hydrochloride (SB269970) 3 μg blocked antinociception by systemic amitriptyline, but it did not prevent antinociception in adenosine A₁ receptor -/- mice. In normal mice, flinching was unaltered when the selective 5-HT₇ receptor agonist (2S)-(+)-5-(1,3,5- trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS-19) 20 μg was administered alone, but increased when co-administered intrathecally with DPCPX 10 nmol or SB269970 3 μg. Intrathecal AS-19 decreased flinching in adenosine A₁ receptor +/+ mice compared to -/- mice. Systemic amitriptyline appears to reduce nociception by activating spinal adenosine A₁ receptors secondarily to 5-HT₇ receptors. Spinal actions constitute only one aspect of antinociception by amitriptyline, as intraplantar DPCPX 10 nmol blocked antinociception by systemic amitriptyline in normal and adenosine A₁ receptor +/+, but not -/- mice. Adenosine A₁ receptor interactions are worthy of attention, as chronic oral caffeine (0.1, 0.3 g/L, doses considered relevant to human intake levels) blocked antinociception by systemic amitriptyline in normal mice. In conclusion, adenosine A₁ receptors contribute to antinociception by systemic amitriptyline in both spinal and peripheral compartments.

Original language	English
Pages (from-to)	213-219
Number of pages	7
Journal	European Journal of Pharmacology
Volume	698
Issue number	1-3
DOIs	https://doi.org/10.1016/j.ejphar.2012.10.042
Publication status	Published - Jan 5 2013

Bibliographical note

Funding Information:
This work was funded by a Canadian Institutes of Health Research (CIHR) Grant. Jean Liu was supported by an Honourary Killam Pre-doctoral Scholarship, a Nova Scotia Health Research Foundation Student Research Award, a Dalhousie Medical Research Foundation Molly Neuroscience Award, and a CIHR Frederick Banting and Charles Best Master's Award. We wish to thank Bertil Fredholm (Karolinska Institute, Stockholm, Sweden) who supplied the initial adenosine A 1 receptor knock-out mice, and whose laboratory performed polymerase chain reaction genotyping of our colony mice.

ASJC Scopus Subject Areas

Pharmacology

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

Access to Document

10.1016/j.ejphar.2012.10.042

Cite this

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title = "Spinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors, are involved in antinociception by systemically administered amitriptyline",

abstract = "The present study explored a link between spinal 5-HT7 and adenosine A1 receptors in antinociception by systemic amitriptyline in normal and adenosine A1 receptor knock-out mice using the 2% formalin test. In normal mice, antinociception by systemic amitriptyline 3 mg/kg was blocked by intrathecal administration of the selective adenosine A 1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) 10 nmol. Blockade was also seen in adenosine A1 receptor +/+ mice, but not in -/- mice lacking these receptors. In both normal and adenosine A 1 receptor +/+ mice, the selective 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl) ethyl]pyrrolidine hydrochloride (SB269970) 3 μg blocked antinociception by systemic amitriptyline, but it did not prevent antinociception in adenosine A1 receptor -/- mice. In normal mice, flinching was unaltered when the selective 5-HT7 receptor agonist (2S)-(+)-5-(1,3,5- trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS-19) 20 μg was administered alone, but increased when co-administered intrathecally with DPCPX 10 nmol or SB269970 3 μg. Intrathecal AS-19 decreased flinching in adenosine A1 receptor +/+ mice compared to -/- mice. Systemic amitriptyline appears to reduce nociception by activating spinal adenosine A1 receptors secondarily to 5-HT7 receptors. Spinal actions constitute only one aspect of antinociception by amitriptyline, as intraplantar DPCPX 10 nmol blocked antinociception by systemic amitriptyline in normal and adenosine A1 receptor +/+, but not -/- mice. Adenosine A1 receptor interactions are worthy of attention, as chronic oral caffeine (0.1, 0.3 g/L, doses considered relevant to human intake levels) blocked antinociception by systemic amitriptyline in normal mice. In conclusion, adenosine A1 receptors contribute to antinociception by systemic amitriptyline in both spinal and peripheral compartments.",

author = "Jean Liu and Reid, {Allison R.} and Jana Sawynok",

note = "Funding Information: This work was funded by a Canadian Institutes of Health Research (CIHR) Grant. Jean Liu was supported by an Honourary Killam Pre-doctoral Scholarship, a Nova Scotia Health Research Foundation Student Research Award, a Dalhousie Medical Research Foundation Molly Neuroscience Award, and a CIHR Frederick Banting and Charles Best Master's Award. We wish to thank Bertil Fredholm (Karolinska Institute, Stockholm, Sweden) who supplied the initial adenosine A 1 receptor knock-out mice, and whose laboratory performed polymerase chain reaction genotyping of our colony mice.",

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AU - Liu, Jean

AU - Reid, Allison R.

AU - Sawynok, Jana

N1 - Funding Information: This work was funded by a Canadian Institutes of Health Research (CIHR) Grant. Jean Liu was supported by an Honourary Killam Pre-doctoral Scholarship, a Nova Scotia Health Research Foundation Student Research Award, a Dalhousie Medical Research Foundation Molly Neuroscience Award, and a CIHR Frederick Banting and Charles Best Master's Award. We wish to thank Bertil Fredholm (Karolinska Institute, Stockholm, Sweden) who supplied the initial adenosine A 1 receptor knock-out mice, and whose laboratory performed polymerase chain reaction genotyping of our colony mice.

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N2 - The present study explored a link between spinal 5-HT7 and adenosine A1 receptors in antinociception by systemic amitriptyline in normal and adenosine A1 receptor knock-out mice using the 2% formalin test. In normal mice, antinociception by systemic amitriptyline 3 mg/kg was blocked by intrathecal administration of the selective adenosine A 1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) 10 nmol. Blockade was also seen in adenosine A1 receptor +/+ mice, but not in -/- mice lacking these receptors. In both normal and adenosine A 1 receptor +/+ mice, the selective 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl) ethyl]pyrrolidine hydrochloride (SB269970) 3 μg blocked antinociception by systemic amitriptyline, but it did not prevent antinociception in adenosine A1 receptor -/- mice. In normal mice, flinching was unaltered when the selective 5-HT7 receptor agonist (2S)-(+)-5-(1,3,5- trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS-19) 20 μg was administered alone, but increased when co-administered intrathecally with DPCPX 10 nmol or SB269970 3 μg. Intrathecal AS-19 decreased flinching in adenosine A1 receptor +/+ mice compared to -/- mice. Systemic amitriptyline appears to reduce nociception by activating spinal adenosine A1 receptors secondarily to 5-HT7 receptors. Spinal actions constitute only one aspect of antinociception by amitriptyline, as intraplantar DPCPX 10 nmol blocked antinociception by systemic amitriptyline in normal and adenosine A1 receptor +/+, but not -/- mice. Adenosine A1 receptor interactions are worthy of attention, as chronic oral caffeine (0.1, 0.3 g/L, doses considered relevant to human intake levels) blocked antinociception by systemic amitriptyline in normal mice. In conclusion, adenosine A1 receptors contribute to antinociception by systemic amitriptyline in both spinal and peripheral compartments.

AB - The present study explored a link between spinal 5-HT7 and adenosine A1 receptors in antinociception by systemic amitriptyline in normal and adenosine A1 receptor knock-out mice using the 2% formalin test. In normal mice, antinociception by systemic amitriptyline 3 mg/kg was blocked by intrathecal administration of the selective adenosine A 1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) 10 nmol. Blockade was also seen in adenosine A1 receptor +/+ mice, but not in -/- mice lacking these receptors. In both normal and adenosine A 1 receptor +/+ mice, the selective 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl) ethyl]pyrrolidine hydrochloride (SB269970) 3 μg blocked antinociception by systemic amitriptyline, but it did not prevent antinociception in adenosine A1 receptor -/- mice. In normal mice, flinching was unaltered when the selective 5-HT7 receptor agonist (2S)-(+)-5-(1,3,5- trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS-19) 20 μg was administered alone, but increased when co-administered intrathecally with DPCPX 10 nmol or SB269970 3 μg. Intrathecal AS-19 decreased flinching in adenosine A1 receptor +/+ mice compared to -/- mice. Systemic amitriptyline appears to reduce nociception by activating spinal adenosine A1 receptors secondarily to 5-HT7 receptors. Spinal actions constitute only one aspect of antinociception by amitriptyline, as intraplantar DPCPX 10 nmol blocked antinociception by systemic amitriptyline in normal and adenosine A1 receptor +/+, but not -/- mice. Adenosine A1 receptor interactions are worthy of attention, as chronic oral caffeine (0.1, 0.3 g/L, doses considered relevant to human intake levels) blocked antinociception by systemic amitriptyline in normal mice. In conclusion, adenosine A1 receptors contribute to antinociception by systemic amitriptyline in both spinal and peripheral compartments.

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