n-methylnaloxone and Osteosarcoma

We have previously shown that stimulation of peripheral opioid receptors by exogenous opiates counteracts the thermal hyperalgesia elicited by a tibial osteosarcoma due to intraosteal inoculation of NCTC 2472 cells to mice. Aiming to study whether pheripheral endogenous enkephalins could also counteract this painful symptom, we assayed in this model the effects of PL37, an orally active dual inhibitor of enkephalin inactivating enzymes. Oral administration of PL37 (25 mg/kg) completely supressed osteosarcoma-induced thermal hyperalgesia through the activation of micro-opioid receptors, since the administration of cyprodime (1 mg/kg) inhibited its antihyperalgesic effect. Neither naltrindole (0.1 mg/kg) nor nor-binaltorphimine (10 mg/kg) modified this PL37-induced antihyperalgesic effect. Moreover, the inhibition of the antihyperalgesic effect induced by PL37 after the administration of naloxone-methiodide (2 mg/kg), a non selective opioid antagonist that does not cross the blood-brain barrier, demonstrates the involvement of peripheral opioid receptors. In contrast, centrally mediated effects may be detected when assaying a higher dose of PL37 (50 mg/kg). Besides, the administration of gabapentin (6.25-25 mg/kg, i.p.) dose-dependently inhibited osteosarcoma-induced thermal hyperalgesia. Interestingly, the combined administration of subeffective doses of PL37 and gabapentin completely prevented this type of thermal hyperalgesia. An isobolographic analysis of this interaction demonstrated a synergistic interaction between both drugs.

Topics: Administration, Oral; Amines; Analgesics; Animals; Bone Neoplasms; Cyclohexanecarboxylic Acids; Disulfides; Drug Synergism; Gabapentin; gamma-Aminobutyric Acid; Hot Temperature; Hyperalgesia; Mice; Naloxone; Neprilysin; Osteosarcoma; Propylamines; Quaternary Ammonium Compounds; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

Previous reports have shown that systemic administration of morphine can prevent the thermal hyperalgesia induced by the development of an osteosarcoma in C3H/HeJ mice after the implantation of NCTC 2472 cells. We show here that this type of hyperalgesia is also abolished by the local administration of morphine given at low doses (10 nmol), or the peripheral acting opioid receptor agonist loperamide (146 nmol). The analgesic effect of loperamide is prevented by the administration of the opioid receptor antagonist naloxone methiodide (10 mg/kg, i.p.), which is unable to cross the blood-brain barrier. These results provide evidence which supports the fact that peripheral opioids could be useful tools in the management of some types of cancer pain.

Topics: Analgesics, Opioid; Animals; Bone Neoplasms; Cell Culture Techniques; Hyperalgesia; Loperamide; Mice; Mice, Inbred C3H; Morphine; Naloxone; Narcotic Antagonists; Osteosarcoma; Pain; Quaternary Ammonium Compounds