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High concentrations of morphine sensitize and activate mouse dorsal root ganglia via TRPV1 and TRPA1 receptors.

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Forster, Alexander B 
Reeh, Peter W 
Messlinger, Karl 
Fischer, Michael JM 


BACKGROUND: Morphine and its derivatives are key drugs in pain control. Despite its well-known analgesic properties morphine at high concentrations may be proalgesic. Particularly, short-lasting painful sensations have been reported upon dermal application of morphine. To study a possible involvement of TRP receptors in the pro-nociceptive effects of morphine (0.3 - 10 mM), two models of nociception were employed using C57BL/6 mice and genetically related TRPV1 and TRPA1 knockout animals, which were crossed and generated double knockouts. Hindpaw skin flaps were used to investigate the release of calcitonin gene-related peptide indicative of nociceptive activation. RESULTS: Morphine induced release of calcitonin gene-related peptide and sensitized the release evoked by heat or the TRPA1 agonist acrolein. Morphine activated HEK293t cells transfected with TRPV1 or TRPA1. Activation of C57BL/6 mouse dorsal root ganglion neurons in culture was investigated with calcium imaging. Morphine induced a dose-dependent rise in intracellular calcium in neurons from wild-type animals. In neurons from TRPV1 and TRPA1 knockout animals activation by morphine was markedly reduced, in the TRPV1/A1 double knockout animals this morphine effect was abrogated. Naloxone induced an increase in calcium levels similar to morphine. The responses to both morphine and naloxone were sensitized by bradykinin. CONCLUSION: Nociceptor activation and sensitization by morphine is conveyed by TRPV1 and TRPA1.



Acrolein, Animals, Bradykinin, Calcitonin Gene-Related Peptide, Calcium Signaling, Capsaicin, Dose-Response Relationship, Drug, Extremities, Ganglia, Spinal, Hot Temperature, Humans, Ion Channel Gating, Mice, Morphine, Naloxone, Neurons, Skin, TRPA1 Cation Channel, TRPV Cation Channels, Transient Receptor Potential Channels

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Mol Pain

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SAGE Publications