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Inhibition of osteosarcoma-induced thermal hyperalgesia in mice by the orally active dual enkephalinase inhibitor PL37. Potentiation by gabapentin.
Eur J Pharmacol. 2008 Oct 31; 596(1-3):50-5.EJ

Abstract

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.

Authors+Show Affiliations

Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, c/ Julián Clavería 6, Oviedo, Asturias, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18692494

Citation

Menéndez, Luis, et al. "Inhibition of Osteosarcoma-induced Thermal Hyperalgesia in Mice By the Orally Active Dual Enkephalinase Inhibitor PL37. Potentiation By Gabapentin." European Journal of Pharmacology, vol. 596, no. 1-3, 2008, pp. 50-5.
Menéndez L, Hidalgo A, Meana A, et al. Inhibition of osteosarcoma-induced thermal hyperalgesia in mice by the orally active dual enkephalinase inhibitor PL37. Potentiation by gabapentin. Eur J Pharmacol. 2008;596(1-3):50-5.
Menéndez, L., Hidalgo, A., Meana, A., Poras, H., Fournié-Zaluski, M. C., Roques, B. P., & Baamonde, A. (2008). Inhibition of osteosarcoma-induced thermal hyperalgesia in mice by the orally active dual enkephalinase inhibitor PL37. Potentiation by gabapentin. European Journal of Pharmacology, 596(1-3), 50-5. https://doi.org/10.1016/j.ejphar.2008.07.043
Menéndez L, et al. Inhibition of Osteosarcoma-induced Thermal Hyperalgesia in Mice By the Orally Active Dual Enkephalinase Inhibitor PL37. Potentiation By Gabapentin. Eur J Pharmacol. 2008 Oct 31;596(1-3):50-5. PubMed PMID: 18692494.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of osteosarcoma-induced thermal hyperalgesia in mice by the orally active dual enkephalinase inhibitor PL37. Potentiation by gabapentin. AU - Menéndez,Luis, AU - Hidalgo,Agustín, AU - Meana,Alvaro, AU - Poras,Hervé, AU - Fournié-Zaluski,Marie-Claude, AU - Roques,Bernard P, AU - Baamonde,Ana, Y1 - 2008/07/30/ PY - 2008/05/08/received PY - 2008/07/11/revised PY - 2008/07/23/accepted PY - 2008/8/12/pubmed PY - 2009/1/13/medline PY - 2008/8/12/entrez SP - 50 EP - 5 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 596 IS - 1-3 N2 - 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. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/18692494/Inhibition_of_osteosarcoma_induced_thermal_hyperalgesia_in_mice_by_the_orally_active_dual_enkephalinase_inhibitor_PL37__Potentiation_by_gabapentin_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(08)00799-1 DB - PRIME DP - Unbound Medicine ER -