Very interesting question!
I think that we first need to distinguish between
'real' antagonists, i.e. compounds that simply block agonistic substances from acting at the receptor, but do
not cause any intracellular response on their own, and
inverse agonists, i.e. compounds that reverse the action of an agonist with concomitant triggering another signal cascade.
Please note in this context that more and more compounds, which were once thought to be antagonists are actually inverse agonists. Some estimations consider the neutral antagonists to be a relatively small group in contrary to the vast majority of antagonistic ligands being inverse agonists. The problem is that often the inverse way of activating the cell is not known yet (hence the still ongoing change in the classification).
Why is the above preface important to consider? I would think that (neutral) antagonists are much less likely to trigger tolerance, because the do not cause any intracellular reaction at all. Inverse agonists on the other do, and whatever their effect may, it is quite realistic to think that tolerance to their effect can developo, too. If this goes contrary to the tolerance of the regular ligand, or if it acts synergistically (as suggested by SlapdragonX for 5HT) must be checked case to case.
Some examples:
Pharmacol Biochem Behav 1995,
50(1), p.9:
Tolerance occurred to the sedative actions of the competitive NMDA antagonists, CGP39551 and CGP37849, as measured by a decrease in spontaneous locomotor activity after 1 wk or 2 wk of administration, resp., in studies using the TO strain of mice. Cross-tolerance was seen between these compds.
Eur J Pharmacol 2007,
560(2-3), p.132:
Ultra-low doses of opioid receptor antagonists inhibit development of chronic spinal morphine tolerance. As this phenomenon mechanistically resembles acute tolerance, the present study examd. actions of opioid receptor antagonists on acute spinal morphine tolerance.
Alimentary Pharmacology and Therapeutics 1990,
4(Suppl. 1), p.47:
Simultaneous 24-h intragastric and plasma gastrin concns. were measured in 36 healthy subjects, when receiving placebo (day 0) and on days 1 and 8 of dosing with either placebo (n = 8 ), or high-dose of H2-blocked with either ranitidine 300 mg q.d.s. (n = 8 ), ranitidine 1200 mg o.m. (n = 8 ) , or sufotidine 600 mg b.d. (n = 12). Triplicate placebo studies demonstrated good reproducibility for this technique, with no significant differences of acidity or plasma gastrin concn. between the studies. There was a decrease in the anti-secretory activity of all 3 high-does H2-antagonist regimens on day 8, when compared with that obsd. on day 1. This occurred in the presence of sustained or increasing hypergastrinemia. It is concluded that a degree of tolerance develops during continued H2-blockade, and that this could be due to increasing gastrin drive to the parietal cells.
Brain Res 1990,
529(1-2), p.143:
Mice treated chronically with opioid antagonists have increased receptor d. in brain and are supersensitive to the pharmacodynamic action of morphine. In the present study mice were implanted s.c. with naltrexone or placebo pellets for 8 days. During implantation mice received daily injections of morphine (100 or 250 mg/kg) or saline. [...] Thus, if naltrexone-induced opioid receptor upregulation occurs in the presence of repeated agonist administration, the new binding sites mediate tolerance via desensitization to morphine.
Eur J Pharmacol 2000,
406(3), p.345:
It is well known that tolerance develops to the actions of caffeine, which acts as an antagonist on adenosine A1 and A2A receptors. Since selective adenosine A2A antagonists have been proposed as adjuncts to 3,4-dihydroxyphenylalanine (l-DOPA) therapy in Parkinson's disease we wanted to examine if tolerance also develops to the selective A2A receptor antagonist 5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo [1,5-c]pyrimidine (SCH 58261). SCH 58261 (0.1 and 7.5 mg/kg) increased basal locomotion and the motor stimulation afforded by apomorphine. Neither effect was subject to tolerance following long-term treatment with the same doses given i.p. twice daily. There were no adaptive changes in A1 and A2A adenosine receptors or their corresponding mRNA or in dopamine D1 or D2 receptors. These results demonstrate that the tolerance that develops to caffeine is not secondary to its inhibition of adenosine A2A receptors. The results also offer hope that long-term treatment with an adenosine A2A receptor antagonist may be possible in man.
And in particular this one:
Mol Pharmacol 1997,
51(3), p.357:
Receptor-mediated endocytosis has been obsd. after agonist occupation of several G protein-coupled receptors, which contributes to the desensitization response to agonist stimulation; however, the cellular signals required to initiate this process are unclear. In this study, the authors developed and characterized a new antagonist analog of cholecystokinin (D-Tyr-Gly-[(Nle28,31,D-Trp30)cholecystokinin-26-32]-phenethyl ester) that can be tagged with a fluorescent rhodamine and radioiodinated. This has permitted the authors to demonstrate that antagonist occupation of the cholecystokinin receptor also results in receptor internalization, which dissocs. this response from second messenger signaling activities and receptor phosphorylation. Immunolocalization of this receptor after occupation with an established nonpeptidyl antagonist confirmed this phenomenon. Antagonist-induced receptor internalization probably results from stabilization of the receptor in a conformation that exposes a domain crit. to directing it into the clathrin-dependent endocytic pathway. This work provides evidence for a new and independent mechanism for receptor internalization, provides a mechanism for the rarely obsd. phenomenon of antagonist-induced desensitization, and raises important issues regarding the approach to establish optimal treatment regimens for antagonist drugs.
Not yet included in this discussion is the part of tolerance caused by the
induction of metabolizing enzymes. This can be caused by agonists, inverse agonists and antagonists alike, as their receptor binding profile is not relevant in this respect. The contrary (i.e. inhibition of metabolizing enzymes) is possible, too.
Examples:
- Fluvoxamine (5HT- & NE-reuptake inhibitor) is both a CYP1A2-substrate and -inhibitor.
- Carbamazepin is both a CYP3A4-substrate and -inductor.
Peace! -
Murphy
