The inhibition of the nitric oxide-cGMP-PKG-JNK signaling pathway avoids the development of tolerance to the local antiallodynic effects produced by morphine during neuropathic pain.

Abstract

Tolerance to the local antiallodynic effects of morphine, DPDPE ([D-Pen(2),D-Pen(5)]-Enkephalin) or JWH-015 ((2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone) after their repeated administration during neuropathic pain was evaluated. The role of the nitric oxide-cGMP-protein kinase G (PKG)-c-Jun N-terminal kinase (JNK) signaling pathway on the peripheral morphine-induced tolerance after the chronic constriction of sciatic nerve in mice was also assessed. The mechanical and thermal antiallodynic effects produced by a high dose of morphine, DPDPE or JWH-015 subplantarly administered daily from days 10 to 20 after nerve injury were estimated with the von Frey filaments and cold plate tests. The antiallodynic effects of the repeated administration of morphine combined with a sub-analgesic dose of a selective inducible nitric oxide synthase (NOS2) (L-N(6)-(1-iminoethyl)-lysine; L-NIL), L-guanylate cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; ODQ), PKG ((Rp)-8-(para-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate; Rp-8-pCPT-cGMPs) or JNK (anthra[1,9-cd]pyrazol-6(2H)-one; SP600125) inhibitor from days 10 to 20 after injury were also evaluated. The repeated administration of morphine, but not DPDPE or JWH-015, produced a rapid development of tolerance to its mechanical and thermal antiallodynic effects in sciatic nerve-injured mice. The co-administration of morphine with L-NIL, ODQ, Rp-8-pCPT-cGMPs or SP600125 avoided the development of morphine antiallodynic tolerance after nerve injury. These findings reveal that the repeated local administration of DPDPE or JWH-015 did not induce antinociceptive tolerance after sciatic nerve injury-induced neuropathic pain. Our data also indicate that the peripheral nitric oxide-cGMP-PKG-JNK signaling pathway participates in the development of morphine tolerance after nerve injury and propose the inactivation of this pathway as a promising strategy to avoid morphine tolerance during neuropathic pain.

• Authors: Arnau Hervera, Sergi Leánez, Olga Pol
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 685 Issue 1-3 Pg. 42-51 (Jun 15 2012) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 22546233 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Analgesics, Opioid
• Indoles
• Nitric Oxide
• Morphine
• Enkephalin, D-Penicillamine (2,5)-
• Cyclic GMP-Dependent Protein Kinases
• Cyclic GMP
• JHW 015

Topics

• Analgesics, Opioid (administration & dosage, pharmacology)
• Animals
• Cyclic GMP (metabolism)
• Cyclic GMP-Dependent Protein Kinases (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Tolerance
• Enkephalin, D-Penicillamine (2,5)- (administration & dosage, pharmacology)
• Hot Temperature
• Hyperalgesia (drug therapy, etiology)
• Indoles (administration & dosage, pharmacology)
• MAP Kinase Signaling System (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Morphine (administration & dosage, pharmacology)
• Nitric Oxide (metabolism)
• Sciatic Neuropathy (drug therapy)