Mechanisms involved in the nociception produced by peripheral protein kinase c activation in mice.
Protein kinase C (PKC) is able to phosphorylate several cellular components that serve as key regulatory components in signal transduction pathways of nociceptor excitation and sensitisation. Therefore, the present study attempted to assess some of the mechanisms involved in the overt nociception elicited by peripheral administration of the PKC activator, phorbol 12-myristate 13-acetate (PMA), in mice. The intraplantar (i.pl.) injection of PMA (16-1600 pmol/paw), but not its inactive analogue alpha-PMA, produced a long-lasting overt nociception (up to 45 min), as well as the activation of PKCalpha and PKCepsilon isoforms in treated paws. Indeed, the local administration of the PKC inhibitor GF109203X completely blocked PMA-induced nociception. The blockade of NK1, CGRP, NMDA, beta1-adrenergic, B2 or TRPV1 receptors with selective antagonists partially decreased PMA-induced nociception. Similarly, COX-1, COX-2, MEK or p38 MAP kinase inhibitors reduced the nociceptive effect produced by PMA. Notably, the nociceptive effect promoted by PMA was diminished in animals treated with an antagonist of IL-1beta receptor or with antibodies against TNFalpha, NGF or BDNF, but not against GDNF. Finally, mast cells as well as capsaicin-sensitive and sympathetic fibres, but not neutrophil influx, mediated the nociceptive effect produced by PMA. Collectively, the results of the present study have shown that PMA injection into the mouse paw results in PKC activation as well as a relatively delayed, but long-lasting, overt nociceptive behaviour in mice. Moreover, these results demonstrate that PKC activation exerts a critical role in modulating the excitability of sensory neurons.
Ferreira
Juliano
J
Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, 88015-420 Florianópolis, SC, Brazil. ferreiraj99@bol.com.br
Trichês
Karen M
KM
Medeiros
Rodrigo
R
Calixto
João B
JB
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004533:Egtazic Acid / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006145:Guanethidine / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology*; D010147:Pain Measurement / Q000379:methods; D010446:Peptide Fragments / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism* / Q000502:physiology; D012430:Ruthenium Red / Q000494:pharmacology; D012459:Salicylates / Q000494:pharmacology; D013565:Sympatholytics / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D000700:Analgesics; D000906:Antibodies; D002614:Chelating Agents; D004151:Dipeptides; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; D010446:Peptide Fragments; D012459:Salicylates; D013565:Sympatholytics; C117223:valerylsalicylic acid; D012430:Ruthenium Red; C058636:calcitonin gene-related peptide (8-37); C078949:FK 888; D004533:Egtazic Acid; C020922:4-O-methyl-12-O-tetradecanoylphorbol 13-acetate; D016291:Dizocilpine Maleate; C065679:icatibant; D011433:Propranolol; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D013755:Tetradecanoylphorbol Acetate; D002211:Capsaicin; D001920:Bradykinin; D006145:Guanethidine