dizocilpine-maleate and icatibant

Bradykinin is one of the most potent endogenous algesic substances and its role in pain transmission has been intensively studied in the periphery. However, the action of this peptide in central structures involved in pain transmission remains unclear. Administration of bradykinin (0.25 nmol/site) into the right amygdala of adult male Wistar rats induced thermal hyperalgesia, evaluated in the paw-flick test. Bradykinin-induced hyperalgesia was abolished by co-administration with the B(2) receptor antagonist Hoe 140 (5 pmol/site), the NMDA antagonist MK-801 (5 nmol/site), the cyclooxygenase inhibitor indomethacin (10 nmol/site) and the glial metabolic inhibitor fluorocitrate (1 nmol/site). Since the intra-amygdala administration of bradykinin did not alter spontaneous locomotion in the open-field test, it is unlikely that the current described hyperalgesic effect of bradykinin is due to an unspecific action on motor activity. These findings provide evidence that bradykinin, through activation of amygdalar B(2) receptors induces hyperalgesia and that glutamatergic- and prostanoid-mediated mechanisms are involved in such effect.

Topics: Amygdala; Animals; Behavior, Animal; Bradykinin; Bradykinin Receptor Antagonists; Citrates; Cyclooxygenase Inhibitors; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hyperalgesia; Indomethacin; Male; Motor Activity; Neuroglia; Pain Measurement; Rats; Rats, Wistar

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.

Topics: Adrenergic beta-Antagonists; Analgesics; Animals; Antibodies; Behavior, Animal; Blotting, Western; Bradykinin; Calcitonin Gene-Related Peptide; Capsaicin; Chelating Agents; Dipeptides; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Egtazic Acid; Enzyme Activation; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Extracellular Signal-Regulated MAP Kinases; Guanethidine; Indoles; Male; Mice; Nociceptors; Pain; Pain Measurement; Peptide Fragments; Propranolol; Protein Kinase C; Ruthenium Red; Salicylates; Sympatholytics; Tetradecanoylphorbol Acetate; Time Factors