For the love of paradox: from neurobiology to pharmacology

The acute and chronic effects of certain drugs can often be opposite. For example, in congestive heart failure acute administration of β-adrenoceptor agonists results in beneficial improvement in symptoms of the disease, but their chronic use increases mortality. Conversely, certain β-adrenoceptor antagonists/inverse agonists (β-blockers) initially cause a detrimental response by decreasing cardiac contractility in congestive heart failure, whereas chronic treatment with the same β-blockers improves contractility and survival. Furthermore, this time-dependent reversal of outcomes occurs in nonpharmacological interventions, such as exercise, and can even be observed in the response of plants to pruning or other stressors, with the results being a different short-term versus long-term effect. Here, we review some of these phenomena with a special emphasis on the temporal dissociation of pharmacological effects. Although Francis Colpaert used this knowledge to lead a drug discovery project for an analgesic compound that initially produced hyperalgesia, we focused on examples outside the central nervous system.