The pro-nociceptive effects of remifentanil or surgical injury in mice are associated with a decrease in delta-opioid receptor mRNA levels: Prevention of the nociceptive response by on-site delivery of enkephalins.
The ultra-short-acting mu-opioid receptor (MOR) agonist remifentanil enhances postsurgical pain when used as main anesthetic in animal models and man. Although the mechanism/s involved are poorly characterized, changes in opioid receptor expression could be a relevant feature. Using a mouse model of postoperative pain, we assessed the expression of MOR and delta opioid receptors (DORs) and the efficacy of Herpes Simplex vector-mediated proenkephalin release (SHPE) preventing postoperative nociceptive sensitization induced by remifentanil or surgical incision. We determined MOR and DOR expressions in the dorsal root ganglia and the spinal cord after remifentanil or surgery in CD1 mice, using real-time PCR and Western blotting. We also assessed the effect of SHPE on nociception induced by remifentanil, surgery, and their combination (2 and 7 days after manipulation), using thermal and mechanical tests. Both remifentanil and surgery decreased DOR mRNA levels (up to days 2 and 4, respectively) in the dorsal root ganglia, but not in the spinal cord. No changes were observed in MOR mRNA, or in receptor-protein levels (Western) of either receptor. Pre-treatment with SHPE 7 days before manipulation prevented remifentanil-induced thermal hyperalgesia and mechanical allodynia and the increase in incisional pain observed when surgery was performed under remifentanil anesthesia. SHPE also prevented surgically induced allodynia but not hyperalgesia, which was blocked by the additional administration of RB101, an enkephalinase inhibitor. The study suggests that down-regulation of DOR contributes to remifentanil and surgery-induced nociception, and that postoperative pain is completely reversed by increasing enkephalin levels in the spinal cord and the periphery.
Cabañero
David
D
Anesthesiology Research Unit, Instituto Municipal de Investigaciones Médicas. Universitat Autònoma de Barcelona, Barcelona, Spain.
Célérier
Evelyne
E
García-Nogales
Paula
P
Mata
Marina
M
Roques
Bernard P
BP
Maldonado
Rafael
R
Puig
Margarita M
MM
D000700:Analgesics / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D004195:Disease Models, Animal; D004220:Disulfides / Q000008:administration & dosage; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008738:Methyl Ethers / Q000008:administration & dosage; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D017288:Pain Threshold; D010149:Postoperative Pain / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D010649:Phenylalanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D010880:Piperidines / Q000009:adverse effects; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000235:genetics* / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism; D000077208:Remifentanil; D000077149:Sevoflurane; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D000700:Analgesics; D004220:Disulfides; D004745:Enkephalins; D008738:Methyl Ethers; D010880:Piperidines; D011498:Protein Precursors; D012333:RNA, Messenger; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C029992:proenkephalin; C074024:RB 101; D000077149:Sevoflurane; D010649:Phenylalanine; D000077208:Remifentanil