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The present study investigated the antinociceptive effects of the flavonoid myricitrin in chemical behavioral models of pain in mice and rats. Myricitrin given by i.p. or p.o. routes produced dose-related antinociception when assessed on acetic acidinduced visceral pain in mice. In addition, the i.p. administration of myricitrin exhibited significant inhibition of the neurogenic pain induced by intraplantar (i.pl.) injection of capsaicin. Likewise, myricitrin given by i.p. route reduced the nociception produced by i.pl. injection of glutamate and phorbol myristate acetate (PMA). Western blot analysis revealed that myricitrin treatment fully prevented the protein kinase C (PKC) ␣ and PKC⑀ activation by PMA in mice hind paws. Myricitrin given i.p. also inhibited the mechanical hyperalgesia induced by bradykinin, without affecting similar responses caused by epinephrine and prostaglandin E 2 . The antinociception caused by myricitrin in the acetic acid test was significantly attenuated by i.p. treatment of mice with the nitric oxide precursor, L-arginine. In contrast, myricitrin antinociception was not affected by naloxone (opioid receptor antagonist) or neonatal pretreatment of mice with capsaicin and myricitrin antinociceptive effects is not related to muscle relaxant or sedative action. Together, these results indicate that myricitrin produces pronounced antinociception against chemical and mechanical models of pain in rodents. The mechanisms involved in their actions are not completely understood but seem to involve an interaction with nitric oxide-L-arginine and protein kinase C pathways.

Background and purpose: Receptor subtypes involved in PGE 2 -induced nociception are still controversial. The present study investigated the prostanoid E receptor (EP) subtypes and the protein kinase (PK) pathways involved in the nociception induced by PGE 2 injection in the mouse paw. Experimental approach: Paw-licking and mechanical allodynia were measured in vivo and protein kinase activation ex vivo by Western blots of extracts of paw skin. Key results: Intraplantar (i.pl.) injection of PGE 2 into the mouse paw caused nociceptive behaviour of short duration with mean ED 50 of 1.43 nmol. PGE 2 produced a longer-lasting mechanical allodynia, with an ED 50 of 0.05 nmol. Intraplantar injection of antagonists at EP 3 or EP 4 , but not at EP 1 or EP 2 receptors inhibited PGE 2 -induced paw-licking. Paw-licking caused by PGE 2 was blocked by an inhibitor of PKA but only partially decreased by inhibition of the extracellular-regulated kinase (ERK). Selective inhibitors of PKC, c-Jun N-terminal kinase (JNK) or p38, all failed to affect PGE 2 -induced paw-licking. An EP 3 antagonist inhibited PGE 2 -induced mechanical allodynia. However, inhibitors of PKA, PKC or ERK, but not p38 or JNK, also partially inhibited PGE 2 -induced mechanical allodynia. Western blot analyses confirmed that i.pl. injection of PGE 2 activated PKA, PKCa, and mitogen activated kinases (MAPKs) in the paw. Co-treatment with EP 3 or EP 4 receptor antagonists reduced PGE 2 -induced PKA and ERK, but not PKCa activation. Conclusions and Implications:The present results indicate that the nociceptive behaviour and mechanical allodynia caused by i.pl. PGE 2 are mediated through activation of distinct EP receptors and PK-dependent mechanisms.

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