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


CONCLUSIONS
Nociceptor activation and sensitization by morphine is conveyed by TRPV1 and TRPA1.
Institute of Physiology and Pathophysiology, University of Erlangen-Nürnberg, Universitätsstrasse 17, Erlangen, 91054 Germany. aforster@physiologie1.uni-erlangen.de
Alexander B
AB
Forster
Peter W
PW
Reeh
Karl
K
Messlinger
Michael J M
MJ
Fischer
D000171:Acrolein; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002211:Capsaicin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005121:Extremities; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009270:Naloxone / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D009270:Naloxone; D009020:Morphine; D000171:Acrolein; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D001920:Bradykinin