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** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** CONVENTIONAL DRUGS USED FOR PAIN RELIEF, SEDATION, ANESTHESIA, OR EUTHANASIA IN LIVESTOCK CAN LEAVE HARMFUL RESIDUES IN FOOD OR THE ENVIRONMENT. L-CARVONE AND METHYL SALICYLATE ARE EDIBLE COMPOUNDS FOUND IN MINT PLANTS THAT ARE GENERALLY RECOGNIZED AS SAFE. YET, PRELIMINARY WORK IN OUR LAB HAS SHOWN THESE MINT EXTRACTS CAN AFFECT CELLULAR TARGETS KNOWN TO BE IMPORTANT FOR ANESTHETIC AND ANALGESIA ACTIVITY. MOREOVER, OUR PILOT STUDIES IN LABORATORY RODENTS DEMONSTRATE THAT THESE MINT EXTRACTS CAN PRODUCE GENERAL ANESTHESIA OR EUTHANASIA. IN THE PROJECT, WE PREDICT THAT L-CARVONE AND METHYL SALICYLATE CAN PRODUCE ANALGESIA, ANESTHESIA, AND EUTHANASIA IN SHEEP, AND THAT CHEMICALLY-RELATED COMPOUNDSCAN SHOW SIMILAR OR EVEN GREATER EFFIECTS ATCELL RECEPTORS RESPONSIBLE FOR THESE EFFECTS. IN AIM 1, WE WILL ADMINISTER L-CARVONE OR METHYL SALICYLATE VIA DIFFERENT ROUTES TO ADULT SHEEP, MEASURE DRUG CONCENTRATIONS IN BLOOD OVER TIME, AND FIT DATA TO A PHARMACOKINETIC MODEL DESCRIBING DRUG UPTAKE, DISTRIBUTION, AND ELIMINATION. IN AIM 2, WE WILL STUDY THE PHARMACOLOGIC AND PHYSIOLOGIC EFFECTS OF L-CARVONE AND METHYL SALICYLATE IN SHEEP. FIRST, WE WILL MEASURETHE BLOOD CONCENTRATION OF EACH DRUG REQUIRED TO PREVENT MOVEMENT IN RESPONSE TO NOXIOUSSTIMULI. ANALGESIC EFFICACY WILL BE TESTED USING DEVICES DESIGNED TO ELICIT BEHAVIORAL RESPONSES TO TEMPERATURE OR PRESSURE STIMULI, AND THESE BEHAVIORAL RESPONSES WILL BECORRELATED TO BLOOD DRUG CONCENTRATIONS. EUTHANASIA WILL BE STUDIED BY MEASURING ELECTROENCEPHALOGRAPHIC AND CARDIORESPIRATORY RESPONSES FOLLOWING IV BOLUS INJECTION OF EACH COMPOUND. IN AIM 3, WE WILL USE STANDARD CELL ELECTROPHYSIOLOGY METHODS TO STUDY THE EFFECTS OF OTHER PLANT-DERIVED RELATIVESOF L-CARVONE AND METHYL SALICYLATEON ION CHANNELS IMPORTANT TO ANALGESIC AND ANESTHETIC ACTIVITY. THIS WILL REVEAL DRUG STRUCTURE-ACTIVITY RELATIONSHIPS KEY TO IDENTIFYING NEW PHARMACEUTICS OF FOOD ORIGIN.

$650,000FY2022National Institute of Food and AgricultureUSDA

University Of California, Davis

Investigators

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** AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** CONVENTIONAL DRUGS USED FOR PAIN RELIEF, SEDATION, ANESTHESIA, OR EUTHANASIA IN LIVESTOCK CAN LEAVE HARMFUL RESIDUES IN FOOD OR THE ENVIRONMENT. L-CARVONE AND METHYL SALICYLATE ARE EDIBLE COMPOUNDS FOUND IN MINT PLANTS THAT ARE GENERALLY RECOGNIZED AS SAFE. YET, PRELIMINARY WORK IN OUR LAB HAS SHOWN THESE MINT EXTRACTS CAN AFFECT CELLULAR TARGETS KNOWN TO BE IMPORTANT FOR ANESTHETIC AND ANALGESIA ACTIVITY. MOREOVER, OUR PILOT STUDIES IN LABORATORY RODENTS DEMONSTRATE THAT THESE MINT EXTRACTS CAN PRODUCE GENERAL ANESTHESIA OR EUTHANASIA. IN THE PROJECT, WE PREDICT THAT L-CARVONE AND METHYL SALICYLATE CAN PRODUCE ANALGESIA, ANESTHESIA, AND EUTHANASIA IN SHEEP, AND THAT CHEMICALLY-RELATED COMPOUNDSCAN SHOW SIMILAR OR EVEN GREATER EFFIECTS ATCELL RECEPTORS RESPONSIBLE FOR THESE EFFECTS. IN AIM 1, WE WILL ADMINISTER L-CARVONE OR METHYL SALICYLATE VIA DIFFERENT ROUTES TO ADULT SHEEP, MEASURE DRUG CONCENTRATIONS IN BLOOD OVER TIME, AND FIT DATA TO A PHARMACOKINETIC MODEL DESCRIBING DRUG UPTAKE, DISTRIBUTION, AND ELIMINATION. IN AIM 2, WE WILL STUDY THE PHARMACOLOGIC AND PHYSIOLOGIC EFFECTS OF L-CARVONE AND METHYL SALICYLATE IN SHEEP. FIRST, WE WILL MEASURETHE BLOOD CONCENTRATION OF EACH DRUG REQUIRED TO PREVENT MOVEMENT IN RESPONSE TO NOXIOUSSTIMULI. ANALGESIC EFFICACY WILL BE TESTED USING DEVICES DESIGNED TO ELICIT BEHAVIORAL RESPONSES TO TEMPERATURE OR PRESSURE STIMULI, AND THESE BEHAVIORAL RESPONSES WILL BECORRELATED TO BLOOD DRUG CONCENTRATIONS. EUTHANASIA WILL BE STUDIED BY MEASURING ELECTROENCEPHALOGRAPHIC AND CARDIORESPIRATORY RESPONSES FOLLOWING IV BOLUS INJECTION OF EACH COMPOUND. IN AIM 3, WE WILL USE STANDARD CELL ELECTROPHYSIOLOGY METHODS TO STUDY THE EFFECTS OF OTHER PLANT-DERIVED RELATIVESOF L-CARVONE AND METHYL SALICYLATEON ION CHANNELS IMPORTANT TO ANALGESIC AND ANESTHETIC ACTIVITY. THIS WILL REVEAL DRUG STRUCTURE-ACTIVITY RELATIONSHIPS KEY TO IDENTIFYING NEW PHARMACEUTICS OF FOOD ORIGIN. · GrantIndex