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.