Opioids are the best analgesics for moderate to severe pain, but their prolonged use leads to adverse effects such as the development of tolerance and physical dependence. Our overall goal is to develop a novel analgesic that does not produce these intolerable side effects. One promising strategy is to target the putative mu-delta receptor heterodimer. In vivo research indicates that antagonism of the delta receptor diminished the development of tolerance and dependence during chronic morphine administration. It has been suggested that receptor dimerization might be involved in this effect. The hypothesis to be tested is that the development of tolerance and physical dependence to opioid agonist-antagonist bivalent ligands is dependent on the distance between the two pharmacophores. The following specific aims are designed to test this hypothesis: (1) To evaluate the effects of acutely administered opioid receptor bivalent ligands with variable spacer lengths on thermal pain. (2) To evaluate the effects of acutely administered opioid receptor bivalent ligands with variable spacer lengths on inflammatory pain. (3) To determine whether tolerance and physical dependence develop during chronic administration of the opioid receptor bivalent ligands.
| Lenard, Natalie R; Daniels, David J; Portoghese, Philip S et al. (2007) Absence of conditioned place preference or reinstatement with bivalent ligands containing mu-opioid receptor agonist and delta-opioid receptor antagonist pharmacophores. Eur J Pharmacol 566:75-82 |
| Lenard, Natalie R; Prpic, Veronica; Adamson, Aaron W et al. (2006) Differential coupling of beta3A- and beta3B-adrenergic receptors to endogenous and chimeric Galphas and Galphai. Am J Physiol Endocrinol Metab 291:E704-15 |
| Daniels, David J; Lenard, Natalie R; Etienne, Chris L et al. (2005) Opioid-induced tolerance and dependence in mice is modulated by the distance between pharmacophores in a bivalent ligand series. Proc Natl Acad Sci U S A 102:19208-13 |
| Lenard, Natalie R; Roerig, Sandra C (2005) Development of antinociceptive tolerance and physical dependence following morphine i.c.v. infusion in mice. Eur J Pharmacol 527:71-6 |
