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Serotonin 5‐HT 1A Receptor Activity of Kratom Alkaloids Mitragynine, Paynantheine, and Speciogynine
Author(s) -
Obeng Samuel,
León Francisco,
Patel Avi,
Restrepo Luis,
GamezJimenez Lea,
Zuarth Gonzalez Julio,
Pallares Victoria,
Mottinelli Marco,
LoperaLondoño Carolina,
McCurdy Christopher,
McMahon Lance,
Hiranita Takato
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.04764
Subject(s) - 5 ht receptor , serotonin , chemistry , pharmacology , traditional medicine , receptor , biology , medicine , biochemistry
Kratom alkaloids have received attention due to their µ‐opioid receptor (MOR) activity whereas the anecdotal use of kratom to improve mood might suggest activity of kratom at serotonin (5‐HT) receptors. Here we compared the in vitro and in vivo activity of four kratom alkaloids [mitragynine (MG), paynantheine (PN), speciogynine (SG), and speciociliatine (SC)] at µ‐opioid and 5‐HT receptor subtypes. I n vitro displacement of [ 3 H]DAMGO at human MOR yielded the rank order affinity (K i s: nM) of morphine (4.2) > fentanyl (8.0) > SC (344) > SG (355) > MG (709) > PN (4,050). Stimulation of [ 35 S]GTPγS binding yielded the rank order efficacy (% stimulation normalized to DAMGO) of fentanyl (110) > morphine (92) > SC (15) > SG, PN, and MG (<5.0). Among six 5‐HT receptor subtypes tested (1A, 1B, 2A, 2B, 2C, and 3), submicromolar affinity was found at 5‐HT 1A and 5‐HT 2B subtypes. I n vitro displacement of [ 3 H]8‐OH‐DPAT at human 5‐HT 1A receptor yielded the rank order affinity of PN (32) > SG (39) > MG and SC (>1,000). I n vitro displacement of [ 125 I]DOI at human 5‐HT 2B receptor yielded the rank order affinity of PN (20) > SG (23) > MG and SC (>1,000). Given the well‐known involvement of 5‐HT 1A receptor in mood disorder, in vivo 5‐HT 1A activity was measured by observation of the lower lip retraction (LLR; presence of visible lower incisors) and hotplate (52°C) response latency (antinociception) in rats. Among the kratom alkaloids tested and control 5‐HT 1A (ipsapirone) and µ‐opioid (fentanyl and morphine) receptor agonists, the rank order potency for LLR (cumulative ED 50 s: µmol/kg, i.p.) was ipsapirone (1.1) > SG (23) > PN (26) > MG (62), an effect sensitive to 5‐HT 1A receptor antagonist WAY100635 (0.019 µmol/kg, i.p.). The rank order potency for antinociception (cumulative ED 50 s: µmol/kg, i.v.) was fentanyl (0.077) > morphine (5.1) > SC (6.3) > ipsapirone (8.5) > PN (11) > SG (15). Mitragynine was not antinociceptive up to its lethal dose 14 µmol/kg (i.v.). In marked contrast to fentanyl, morphine, and SC, the antinociceptive effects of ipsapirone, SG, and PN were irreversible with the opioid antagonist naltrexone (0.085 µmol/kg, i.p.). In rats discriminating morphine (4.2 µmol/kg, i.p.) from vehicle, the rank order drug‐lever responding (%) was morphine and fentanyl (100) > SC (92) > MG (72) > SG (50) > PN (46). The rank order potency for drug‐lever responding (ED 50 s: µmol/kg) was morphine (2.4) > fentanyl (5.9) > SC (49) > MG (68) > SG (136). Analyzing the affinity at 5‐HT1A and µ‐opioid receptors and in vivo potency, the highest correlation was found between 5‐HT1A affinity and potency for LLR (P=0.0508). These results suggest the 5‐HT 1A activity of SG, PN and MG might contribute to the potential implication of kratom for mood improvement.