Interaction between the spinal melanocortin and opioid systems in a rat model of neuropathic pain.
BACKGROUND
The authors recently demonstrated that administration of the melanocortin-4 receptor antagonist SHU9119 decreased neuropathic pain symptoms in rats with a sciatic chronic constriction injury. The authors hypothesised that there is a balance between tonic pronociceptive effects of the spinal melanocortin system and tonic antinociceptive effects of the spinal opioid system. Therefore, they investigated a possible interaction between these two systems and tested whether opioid effectiveness could be increased through modulation of the spinal melanocortin system activity.


METHODS
In chronic constriction injury rats, melanocortin and opioid receptor ligands were administered through a lumbar spinal catheter, and their effects on mechanical allodynia were assessed by von Frey probing.


RESULTS
Naloxone (10-100 microg) dose-dependently increased allodynia (percent of maximum possible effect of -67 +/- 9%), which is in agreement with a tonic antinociceptive effect of the opioid system. SHU9119 decreased allodynia (percent of maximum possible effect of 60 +/- 13%), and this effect could be blocked by a low dose of naloxone (0.1 microg), which by itself had no effect on withdrawal thresholds. Morphine (1-10 microg) dose-dependently decreased allodynia (percent of maximum possible effect of 73 +/- 14% with the highest dose tested). When 0.5 microg SHU9119 (percent of maximum possible effect of 47 +/- 14%) was given 15 min before morphine, there was an additive antiallodynic effect of both compounds.


CONCLUSIONS
Together, these data confirm that there is an interaction between the spinal melanocortin and opioid systems and that combined treatment with melanocortin-4 receptor antagonists and opioids might possibly contribute to the treatment of neuropathic pain.
Vrinten
Dorien H
DH
Department of Medical Pharmacology and Anesthesiology, Rudolf Magnus Institute for Neurosciences, University Medical Center Utrecht, Utrecht, The Netherlands. d.h.vrinten@med.uu.nl
Gispen
Willem Hendrik
WH
Kalkman
Cor J
CJ
Adan
Roger A H
RA
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004347:Drug Interactions; D004723:Endorphins / Q000502:physiology*; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism* / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology*; D010812:Physical Stimulation; D051381:Rats; D017208:Rats, Wistar; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000037:antagonists & inhibitors; D012684:Sensory Thresholds / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism*; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology
D000701:Analgesics, Opioid; D004723:Endorphins; D009292:Narcotic Antagonists; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; C081720:alpha-MSH (4-10)amide, Ac-Nle(4)-cyclo(Asp(5)-Phe(7)-Lys(10))-; C103272:SHU 9119; D009270:Naloxone; D000521:alpha-MSH; D009020:Morphine; D009074:Melanocyte-Stimulating Hormones