Spinal effect of a neuropeptide FF analogue on hyperalgesia and morphine-induced analgesia in mononeuropathic and diabetic rats.
1DMe, a neuropeptide FF (NPFF) analogue, has been shown to produce antinociception and to enhance morphine analgesia in rats after intrathecal administration. To determine whether 1DMe could correct hyperalgesia and restore morphine efficacy in mononeuropathic (MN) and diabetic (D) rats we examined the spinal effect of 1DMe in MN and D rats without and after spinal blockade of mu- and delta-opioid receptors with CTOP and naltrindole, respectively. The influence of 1DMe on morphine-induced antinociception was assessed in the two models using isobolographic analysis. Whereas 1DMe intrathecally injected (0.1, 1, 7.5 microg rat(-1)) was ineffective in normal (N) rats, it suppressed mechanical hyperalgesia (decrease in paw pressure-induced vocalisation thresholds) in both MN and D rats. This effect was completely cancelled by CTOP (10 microg rat(-1)) and naltrindole (1 microg rat(-1)) suggesting that it requires the simultaneous availability of mu- and delta-opioid receptors. The combinations of morphine: 1DMe (80.6:19.4% and 99.8:0.2%, in MN and D rats, respectively) followed by isobolographic analysis, showed a superadditive interaction, relative to the antinociceptive effect of single doses, in D rats only. In N rats, the combination of morphine: 1DMe (0.5 mg kg(-1), i.v.: 1 microg rat(-1), i.t., ineffective doses) resulted in a weak short-lasting antinociceptive effect. These results show a different efficacy of 1DMe according to the pain model used, suggesting that the pro-opioid effects of the NPFF in neuropathic pain are only weak, which should contribute to hyperalgesia and to the impaired efficacy of morphine.
Courteix
C
C
Equipe NPPUA, INSERM E9904, Laboratoire de Pharmacologie, Faculté de Pharmacie, Clermont-Ferrand, France.
Coudoré-Civiale
M A
MA
Privat
A M
AM
Zajac
J M
JM
Eschalier
A
A
Fialip
J
J
D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006930:Hyperalgesia / Q000503:physiopathology* / Q000517:prevention & control; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009422:Nervous System Diseases / Q000503:physiopathology*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010146:Pain / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D013004:Somatostatin / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D014828:Vocalization, Animal / Q000187:drug effects
D000700:Analgesics; D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009842:Oligopeptides; C049352:phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide; C080757:tyrosyl-leucyl-N-methylphenylalanyl-glutaminyl-prolyl-glutaminyl-arginyl-phenylalaninamide; D013004:Somatostatin; D009271:Naltrexone; D009020:Morphine; C053651:phenylalanyl-leucyl-phenylalanyl-glutaminyl-prolyl-glutaminyl-arginyl-phenylalaninamide; C055382:naltrindole