A prolonged protein kinase C-mediated, opioid-related antinociceptive effect of st John's Wort in mice.
The antinociceptive profile of St. John's Wort (SJW) was investigated in mice in a condition of acute thermal and chemical pain, together with the mechanism that might underlie this effect. A dried extract of SJW induced a prolonged antinociception that persisted for 120 minutes after administration. The thermal antinociception was prevented by naloxone and by the protein kinase C (PKC) activator PMA, whereas the chemical antinociception was prevented by PMA, remaining naloxone insensitive. A chloroform (CHL) and a methanol (MET) fraction, obtained to investigate the involvement of the SJW main components, hyperforin and hypericin/flavonoid, respectively, increased pain threshold with a time course comparable to the dried extract. The CHL antinociception was prevented by naloxone, whereas the MET antinociception was antagonized by PMA. Purified hyperforin and hypericin showed an antinociceptive efficacy comparable to CHL and MET, respectively. Conversely, flavonoids were devoid of any effect. The administration of yohimbine and atropine did not modify SJW, CHL and MET antinociception. These results indicate that both CHL and MET fractions mediate the SJW-induced antinociception. In particular, the presence of hypericin was fundamental to induce both thermal and chemical antinociception through the inhibition of the PKC activity, whereas hyperforin selectively produced a thermal opioid antinociception.


CONCLUSIONS
This article presents evidence of a persistent thermal and chemical antinociception of SJW that is mainly mediated by PKC-inhibiting mechanisms. These findings identify important targets for a longer-acting activation of endogenous pain systems and should potentially help clinicians who seek safe, tolerable, and prolonged treatments for pain relief.
Galeotti
Nicoletta
N
Department of Preclinical and Clinical Pharmacology, University of Florence, Viale G. Pieraccini 6, I-50 139 Florence, Italy. nicoletta.galeotti@unifi.it
Vivoli
Elisa
E
Bilia
Anna Rita
AR
Bergonzi
Maria Camilla
MC
Bartolini
Alessandro
A
Ghelardini
Carla
C
D019342:Acetic Acid / Q000009:adverse effects; D000700:Analgesics / Q000494:pharmacology / Q000627:therapeutic use*; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000873:Anthracenes; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D004339:Drug Compounding / Q000379:methods; D020902:Hypericum / Q000737:chemistry*; D008297:Male; D051379:Mice; D009270:Naloxone / Q000009:adverse effects; D009271:Naltrexone / Q000009:adverse effects / Q000031:analogs & derivatives; D009292:Narcotic Antagonists / Q000009:adverse effects; D010146:Pain / Q000209:etiology / Q000517:prevention & control*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D010569:Perylene / Q000031:analogs & derivatives / Q000627:therapeutic use; D010703:Phorbol Esters / Q000627:therapeutic use; D008517:Phytotherapy / Q000379:methods*; D011493:Protein Kinase C / Q000378:metabolism*; D011794:Quercetin / Q000031:analogs & derivatives / Q000627:therapeutic use; D013004:Somatostatin / Q000009:adverse effects / Q000031:analogs & derivatives; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D018709:Statistics, Nonparametric; D013997:Time Factors
D000700:Analgesics; D000701:Analgesics, Opioid; D000873:Anthracenes; D009292:Narcotic Antagonists; D010703:Phorbol Esters; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; D009270:Naloxone; C051844:norbinaltorphimine; D013004:Somatostatin; D010569:Perylene; D009271:Naltrexone; C004965:hypericin; C032974:12-O-retinoylphorbol-13-acetate; C021304:hyperoside; D011794:Quercetin; D011493:Protein Kinase C; D019342:Acetic Acid