Evidence that mu-opioid receptors mediate midbrain "stimulation-produced analgesia" in the freely moving rat.
Electrical stimulation of the ventral midbrain in freely moving rats led to an antinociception against both noxious heat and noxious pressure. Recurrent stimulation was associated with a progressive loss of the antinociceptive efficacy of stimulation. Rats adapted ("tolerant") to stimulation revealed a significant reduction in the antinociceptive potency of a low dose of the systemically applied selective mu-opioid agonist, morphine. In distinction, the antinociceptive effect of the selective kappa-agonist, trans-3,4-dichloro-N-methyl-N[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetam ide (U50488H) was not modified. In the presence of naloxone, delivered subcutaneously via minipumps at a low dose for 7 days, the antinociceptive action of morphine was abolished, whereas that of U50488H was not attenuated: this reflects the selective blockade of mu-receptors. Rats receiving naloxone failed to develop an antinociception upon midbrain electrical stimulation. Removal of the pumps led to a supersensitivity to the antinociceptive effects of morphine but not U50488H. Similarly, midbrain stimulation-produced antinociception was enhanced. These data demonstrate that (1) midbrain stimulation-produced analgesia is selectively cross-tolerant to a mu- as compared to a kappa-agonist; (2) a very low dose of naloxone selective for the mu-receptor blocks midbrain stimulation-produced analgesia, and (3) chronic naloxone treatment leads to a selective supersensitivity to a mu-agonist as compared to a kappa-agonist and an enhancement of midbrain stimulation-produced analgesia. Collectively, the data indicate that a mu-opioid receptor mediates midbrain stimulation-produced analgesia in the rat against both noxious heat and noxious pressure.
Millan
M J
MJ
Department of Neuropharmacology, Max-Planck-Institut für Psychiatrie, Martinsried, F.R.G.
Członkowski
A
A
Herz
A
A
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000698:Analgesia; D000818:Animals; D004558:Electric Stimulation; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000502:physiology*; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity; D009270:Naloxone / Q000008:administration & dosage / Q000494:pharmacology; D010146:Pain / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D011759:Pyrrolidines; D011957:Receptors, Opioid; D009270:Naloxone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D009020:Morphine