Involvement of nitric oxide in the inhibition of bone cancer-induced hyperalgesia through the activation of peripheral opioid receptors in mice

Experiments were designed to elucidate the involvement of nitric oxide (NO) in the antihyperalgesic effect induced by the activation of peripheral μ-opioid receptors on osteosarcoma-induced thermal hyperalgesia in mice. Since this pathway has previously been shown to be involved in the antihyperalgesic effect induced by some drugs—including opiates—on inflammatory pain, experiments were also performed in inflamed mice. The intraplantar administration of loperamide (15 μg) abolishes the thermal hyperalgesia that appears 4 weeks after the intratibial inoculation of NCTC 2472 cells in C3H/HeJ mice. The blockade of this effect by coadministering a peripheral opioid receptor antagonist (naloxone methiodide), a nitric oxide synthase (NOS) inhibitor (L-NMMA), a soluble guanylyl cyclase inhibitor (ODQ), a PKG inhibitor (KT-5823) or a K+ATP-channel blocker (glibenclamide) shows the involvement of a NO/cGMP/K+ATP-channel pathway. Accordingly the administration of loperamide produced, in osteosarcoma-bearing mice, an increase in the concentrations of NO metabolites, nitrites and nitrates, extracted from paws. The selective inhibitor of eNOS L-NIO, but not the inhibitors of nNOS (N-ω-propyl-l-arginine) or iNOS (1400w), blocked the effect of loperamide on osteosarcoma-induced hyperalgesia and also the endogenous opioid peripheral hypoalgesia that appears during the initial stages of the development of this osteosarcoma. Although this pathway also participates in the inhibitory effect of loperamide on the thermal hyperalgesia induced by administration of complete Freund's adjuvant, only selective inhibitors of nNOS or iNOS antagonized this effect. Our results demonstrate that the activation of a NO/cGMP/K+ATP-channel triggered by eNOS participates in the peripheral antihyperalgesic of loperamide on osteosarcoma-induced thermal hyperalgesia.