Inhibition of GTP cyclohydrolase reduces cancer pain in mice and enhances analgesic effects of morphine.
Noncoding polymorphisms of the GTP cyclohydrolase gene (GCH1) reduce the risk for chronic pain in humans suggesting GCH1 inhibitors as analgesics. We assessed the effects of the GCH1 inhibitor diaminohydroxypyrimidine (DAHP) on nociception and inflammation in a mouse melanoma and a sarcoma cancer pain model, and its co-effects with morphine in terms of analgesic efficacy and respiratory depression. GCH1 inhibition did not reduce the tumor-evoked nociceptive hypersensitivity of the tumor-bearing paw. However, DAHP reduced melanoma- and sarcoma-evoked systemic hyperalgesia as determined by analyzing contralateral paws. GCH1 inhibition increased the inflammatory edema and infiltration with polymorphonuclear leukocytes surrounding the tumor but reduced the tumor-evoked microglia activation in the spinal cord suggesting that an increase of the local immune attack against the tumor may avoid general pain hypersensitivity. When used in combination with morphine at high or low doses, GCH1 inhibition increased and prolonged the analgesic effects of the opioid. It did not, however, increase the respiratory depression caused by morphine. Conversely, the GCH1-product, tetrahydrobiopterin, caused hyperalgesia, antagonized antinociceptive effects of morphine, and aggravated morphine-evoked respiratory depression, the latter mimicked by a cGMP analog suggesting that respiratory effects were partly mediated through the BH4-NO-cGMP pathway. The observed effects of GCH1 inhibition in the tumor model and its enhancement of morphine-evoked antinociception without increase of morphine toxicity suggest that GCH1 inhibitors might be useful as co-therapeutics for opioids in cancer patients.
pharmazentrum frankfurt, ZAFES, Institut für Klinische Pharmakologie, Klinikum der Goethe-Universität Frankfurt, Theodor Stern Kai 7, Hs 74, 60590 Frankfurt, Germany.
Geethanjali
G
Pickert
Thekla
T
Myrczek
Steven
S
Rückert
Andreas
A
Weigert
Annett
A
Häussler
Nerea
N
Ferreirós
Bernhard
B
Brüne
Jörn
J
Lötsch
Irmgard
I
Tegeder
D000818:Animals; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D010146:Pain / Q000188:drug therapy* / Q000201:enzymology*; D012509:Sarcoma / Q000188:drug therapy / Q000201:enzymology; D013400:Sugar Acids / Q000627:therapeutic use
C017182:5-dehydro-3-deoxy-D-arabino-heptulosonic acid-7-phosphate; D013400:Sugar Acids; D009020:Morphine; D006136:GTP Cyclohydrolase