Cannabinoid receptor 1 knockout mouse genotype: molecular mechanisms & dependencies

How nutrients influence it

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What it does

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Recorded relationships

Where it participates (unsigned role)

In thermal, mechanical and chemical pain tests the specific cannabinoid receptor 1 antagonist AM-251 abolished the analgesic action of acetaminophen, which was also lost in cannabinoid receptor 1 knockout mice, yet acetaminophen was shown unable to bind to those receptors demonstrating an indirect involvement, inhibition of fatty acid amide hydrolase suppressed the effect, and the antinociceptive activity of a cannabinoid receptor 1 agonist was itself inhibited by lesion of bulbospinal serotonergic pathways and by spinal 5-HT receptor antagonists, leading the authors to propose a sequence of metabolism to AM404, indirect cannabinoid receptor involvement, reinforcement of serotonergic bulbospinal pathways and action at spinal serotonergic receptors.
Human cannabinoid receptor 1 / CB1 / CNR1 → Antinociception in thermal, mechanical and chemical pain tests source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/paracetamol-research/18485596.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9bd927cbceffd6cf3a23e34bb0a6ce1584f989173a383745a97b82222f89798f", "start_char": 0, "end_char": 1545, "text_sha256": "9bd927cbceffd6cf3a23e34bb0a6ce1584f989173a383745a97b82222f89798f"}
experimental_model
Thermal, mechanical and chemical pain tests in cannabinoid receptor 1 knockout mice with receptor binding and pathway lesions
exposure
Acetaminophen with AM-251, cannabinoid receptor 1 deletion, fatty acid amide hydrolase inhibition and serotonergic pathway lesion
limitations
The binding experiment is what makes the receptor involvement indirect rather than direct, which is the substantive point. The proposed sequence is the authors’ synthesis.
nutrient_topic
Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol
organism
Mouse
plain_language
The drug needs the cannabinoid receptor but never touches it, which is what a metabolite doing the work looks like.
primary_references
[apap-p18485596] Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. (2008). https://pubmed.ncbi.nlm.nih.gov/18485596/ DOI: 10.1016/j.pain.2008.03.030
tissue_or_cell_type
Brain and spinal cord
Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 337–348
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Thermal, mechanical and chemical pain tests in cannabinoid receptor 1 knockout mice with receptor binding and pathway lesions · source_derived_draft · unverified_draft
### apap-cb1-needed-but-not-bound In thermal, mechanical and chemical pain tests the specific cannabinoid receptor 1 antagonist AM-251 abolished the analgesic action of acetaminophen, which was also lost in cannabinoid receptor 1 knockout mice, yet acetaminophen was shown unable to bind to those receptors demonstrating an indirect involvement, inhibition of fatty acid amide hydrolase suppressed the effect, and the antinociceptive activity of a cannabinoid receptor 1 agonist was itself inhibited by lesion of bulbospinal serotonergic pathways and by spinal 5-HT receptor antagonists, leading the authors to propose a sequence of metabolism to AM404, indirect cannabinoid receptor involvement, reinforcement of serotonergic bulbospinal pathways and action at spinal serotonergic receptors. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The drug needs the cannabinoid receptor but never touches it, which is what a metabolite doing the work looks like. organism: Mouse tissue_or_cell_type: Brain and spinal cord experimental_model: Thermal, mechanical and chemical pain tests in cannabinoid receptor 1 knockout mice with receptor binding and pathway lesions limitations: The binding experiment is what makes the receptor involvement indirect rather than direct, which is the substantive point. The proposed sequence is the authors’ synthesis. exposure: Acetaminophen with AM-251, cannabinoid receptor 1 deletion, fatty acid amide hydrolase inhibition and serotonergic pathway lesion evidence_span: {"source_cache": "artifacts/paracetamol-research/18485596.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9bd927cbceffd6cf3a23e34bb0a6ce1584f989173a383745a97b82222f89798f", "start_char": 0, "end_char": 1545, "text_sha256": "9bd927cbceffd6cf3a23e34bb0a6ce1584f989173a383745a97b82222f89798f"} [apap-p18485596] Endocannabinoid and serotonergic systems are needed for acetaminophen-induced analgesia. (2008). https://pubmed.ncbi.nlm.nih.gov/18485596/ DOI: 10.1016/j.pain.2008.03.030
Complete structured claim and evidence
Paracetamol induced hypothermia to the same extent in cannabinoid receptor 1 and TRPV1 knockout mice as in wild-type mice and to the same extent in mice pretreated with the antagonists AM251 or SB366791 as in controls, AM404 failed to induce hypothermia at pharmacological doses, inhibition of fatty acid amide hydrolase did not prevent the development of hypothermia and paracetamol induced hypothermia in fatty acid amide hydrolase knockout mice to the same extent as in wild-type mice, so paracetamol induces hypothermia independent of cannabinoids and TRPV1 and AM404 does not mediate this response.
AM404 / N-arachidonoylphenolamine → Hypothermia induced by paracetamol below normal body temperature source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/paracetamol-research/21628499.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "784e57af3594f8d46b3b9fa70cdbc69451f9c2d424253c3b69b216d7cc541613", "start_char": 0, "end_char": 1809, "text_sha256": "784e57af3594f8d46b3b9fa70cdbc69451f9c2d424253c3b69b216d7cc541613"}
experimental_model
Body temperature after paracetamol in cannabinoid receptor 1 and TRPV1 knockout mice with antagonists and fatty acid amide hydrolase manipulation
exposure
300 milligrams per kilogram paracetamol in knockouts and after AM251 or SB366791, with AM404 given directly
limitations
Applies the same knockout logic used for analgesia to a different endpoint and gets the opposite answer, which is why both are recorded. Hypothermia below normal is not the same endpoint as antipyresis in fever.
nutrient_topic
Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. · Paracetamol
organism
Mouse
plain_language
The same knockouts that abolish the painkilling leave the temperature drop completely untouched.
primary_references
[apap-p21628499] Paracetamol-induced hypothermia is independent of cannabinoids and transient receptor potential vanilloid-1 and is not mediated by AM404. (2011). https://pubmed.ncbi.nlm.nih.gov/21628499/ DOI: 10.1124/dmd.111.038638
tissue_or_cell_type
Whole body temperature
Paracetamol: the enzyme it reduces rather than blocks, the isoform that turned out not to exist, the metabolite that carries the analgesia, and the metabolite that destroys the liver (2026-09-22) · lines 376–387
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Body temperature after paracetamol in cannabinoid receptor 1 and TRPV1 knockout mice with antagonists and fatty acid amide hydrolase manipulation · source_derived_draft · unverified_draft
### apap-hypothermia-is-a-different-mechanism Paracetamol induced hypothermia to the same extent in cannabinoid receptor 1 and TRPV1 knockout mice as in wild-type mice and to the same extent in mice pretreated with the antagonists AM251 or SB366791 as in controls, AM404 failed to induce hypothermia at pharmacological doses, inhibition of fatty acid amide hydrolase did not prevent the development of hypothermia and paracetamol induced hypothermia in fatty acid amide hydrolase knockout mice to the same extent as in wild-type mice, so paracetamol induces hypothermia independent of cannabinoids and TRPV1 and AM404 does not mediate this response. Condition category: normal nutrient_topic: Paracetamol research collection; topical membership is not evidence of a direct clinical effect, and the drug is recorded separately from the metabolites NAPQI and AM404. plain_language: The same knockouts that abolish the painkilling leave the temperature drop completely untouched. organism: Mouse tissue_or_cell_type: Whole body temperature experimental_model: Body temperature after paracetamol in cannabinoid receptor 1 and TRPV1 knockout mice with antagonists and fatty acid amide hydrolase manipulation limitations: Applies the same knockout logic used for analgesia to a different endpoint and gets the opposite answer, which is why both are recorded. Hypothermia below normal is not the same endpoint as antipyresis in fever. exposure: 300 milligrams per kilogram paracetamol in knockouts and after AM251 or SB366791, with AM404 given directly evidence_span: {"source_cache": "artifacts/paracetamol-research/21628499.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "784e57af3594f8d46b3b9fa70cdbc69451f9c2d424253c3b69b216d7cc541613", "start_char": 0, "end_char": 1809, "text_sha256": "784e57af3594f8d46b3b9fa70cdbc69451f9c2d424253c3b69b216d7cc541613"} [apap-p21628499] Paracetamol-induced hypothermia is independent of cannabinoids and transient receptor potential vanilloid-1 and is not mediated by AM404. (2011). https://pubmed.ncbi.nlm.nih.gov/21628499/ DOI: 10.1124/dmd.111.038638
Complete structured claim and evidence

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Open hypotheses

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Cannabinoid receptor 1 knockout mouse genotype