The Journal of pharmacology and experimental therapeutics
-
J. Pharmacol. Exp. Ther. · Jan 2002
Comparative StudyMorphine tolerance in spinal cord is due to interaction between mu- and delta-receptors.
When the opioid agonist morphine is given chronically and systemically to mice by pellet implantation for 3 days, the animals develop substantial tolerance to the antinociceptive effect of a test dose of morphine given systemically. When the test dose is administered to the spinal cord, however, very little tolerance is observed. We tested six strains of mice differing in the degree to which they develop systemic tolerance to morphine and found that none of them developed significant tolerance to spinal morphine. ⋯ In contrast, in tolerant animals, TIPPpsi enhanced the antinociception of DAMGO. These results thus demonstrate not only that mu- and delta-opioid receptors interact in naïve animals, but that the nature of this interaction changes during tolerance, from a potentiation to an inhibition. The lack of tolerance to spinal morphine may result from the ability of morphine to act as a partial antagonist at delta-receptors.
-
J. Pharmacol. Exp. Ther. · Jan 2002
Randomized Controlled Trial Clinical TrialEffects of subcutaneous methylnaltrexone on morphine-induced peripherally mediated side effects: a double-blind randomized placebo-controlled trial.
Methylnaltrexone, the first peripheral opioid receptor antagonist, has the potential to prevent or reverse opioid-induced peripherally mediated side effects without affecting analgesia. In previous human trials, we demonstrated that intravenous methylnaltrexone prevented morphine-induced delay in gastrointestinal transit time. We also observed that the compound decreased some of the morphine-induced troublesome subjective effects. ⋯ In addition, subcutaneous methylnaltrexone significantly decreased morphine-induced subjective rating changes. Pharmacokinetic data after subcutaneous drug injection were compared to the data obtained from previous intravenous and oral administrations. Our results suggest that subcutaneous methylnaltrexone may have clinical utility in treating opioid-induced constipation and reducing opioid-induced unpleasant subjective symptoms.
-
J. Pharmacol. Exp. Ther. · Jan 2002
Group I metabotropic glutamate receptor antagonists block secondary thermal hyperalgesia in rats with knee joint inflammation.
Activation of ionotropic glutamate receptors has been shown previously to be essential for the development of secondary thermal hyperalgesia. The present study assessed involvement of group I metabotropic glutamate receptors (mGlu) in both the induction and maintenance phases of secondary thermal hyperalgesia initiated by knee joint inflammation in rats. The dose dependence of each drug in antagonism of thermal hypersensitivity was demonstrated in pre- and post-treatment paradigms. ⋯ Post-treatment with the group I mGlu receptor antagonists LY367385 and AIDA allowed significant recovery of the paw withdrawal latencies after the onset of the knee joint inflammation. The knee joint inflammation itself was not affected by either treatment. The results of the present study indicate that secondary thermal hyperalgesia can be effectively attenuated during both the development and maintenance phases of acute knee joint inflammation by spinal application of specific group I mGlu receptor antagonists.
-
J. Pharmacol. Exp. Ther. · Dec 2001
Benzylidene analogs of anabaseine display partial agonist and antagonist properties at the mouse 5-hydroxytryptamine(3A) receptor.
The nicotinic receptor drug candidate, 3-(2,4-dimethoxybenzylidene)-anabaseine (also known as GTS-21; DMXBA), its hydroxy metabolites, and some related analogs were evaluated with the two-electrode voltage-clamp technique in mouse 5-hydroxytryptamine (5-HT)(3A) receptors expressed in Xenopus oocytes. Although DMXBA lacked partial agonist activity, its hydroxy-benzylidene metabolites and related analogs were partial agonists, displaying the following rank order of potency (EC(50)) and apparent efficacy: 5-HT, 0.9 +/- 0.06 microM (100% efficacy) > 3-(2-hydroxy,4-methoxybenzylidene)-anabaseine (2-OH-MBA), 2.0 +/- 0.3 microM (63% efficacy) > 3-(2,4-dihydroxybenzylidene)-anabaseine, 2.6 +/- 0.3 microM (63% efficacy) > 3-(2-methoxy,4-hydroxybenzylidene)-anabaseine, 17.2 +/- 1.0 microM (30% efficacy). To examine the influence of a benzylidene ring hydroxy substituent, the agonist actions of the three possible monohydroxy isomers were examined. ⋯ DMXBA demonstrated both competitive and noncompetitive forms of antagonism over the range of concentrations tested. These results suggest that a hydroxy substituent at the 2' position of the benzene ring is necessary and sufficient for partial agonist activity; substitution at the 4' position with a hydroxy or methoxy group further enhances agonist potency. Because 2-OH-MBA is a primary metabolite of DMXBA, it may contribute to the physiological, biochemical, and behavioral effects of the parent compound when administered in vivo.
-
J. Pharmacol. Exp. Ther. · Dec 2001
ReviewPharmacology of opioid and nonopioid analgesics in chronic pain states.
Chronic pain represents a mixture of pathophysiologic mechanisms, a complex assortment of spontaneous and elicited pain states, and a somewhat unpredictable response to analgesics. Opioids remain the mainstay of treatment of moderate to severe chronic pain, although there is little systematic examination to guide drug selection. Cyclooxygenase inhibitors play primarily an adjunctive role in chronic pain treatment. ⋯ A number of arthritic states have also been produced by means of chronic joint inflammation in rats. The pharmacology of these neuropathic and arthritic pain models generally resembles that found in the respective human conditions. Additional models of chronic pain, particularly visceral pain, have been developed; however, the pharmacology of these models is not well established at this time.