Central serotonergic neurons are differentially required for opioid analgesia but not for morphine tolerance or morphine reward
- 4 September 2007
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 104 (36), 14519-14524
- https://doi.org/10.1073/pnas.0705740104
Abstract
Opioids remain the most effective analgesics despite their potential adverse effects such as tolerance and addiction. Mechanisms underlying these opiate-mediated processes remain the subject of much debate. Here we describe opioid-induced behaviors of Lmx1b conditional knockout mice (Lmx1bf/f/p), which lack central serotonergic neurons, and we report that opioid analgesia is differentially dependent on the central serotonergic system. Analgesia induced by a kappa opioid receptor agonist administered at the supraspinal level was abolished in Lmx1bf/f/p mice compared with their wild-type littermates. Furthermore, compared with their wild-type littermates Lmx1bf/f/p mice exhibited significantly reduced analgesic effects of mu and delta opioid receptor agonists at both spinal and supraspinal sites. In contrast to the attenuation in opioid analgesia, Lmx1bf/f/p mice developed tolerance to morphine analgesia and displayed normal morphine reward behavior as measured by conditioned place preference. Our results provide genetic evidence supporting the view that the central serotonergic system is a key component of supraspinal pain modulatory circuitry mediating opioid analgesia. Furthermore, our data suggest that the mechanisms of morphine tolerance and morphine reward are independent of the central serotonergic system.Keywords
This publication has 54 references indexed in Scilit:
- Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmissionPharmacology & Therapeutics, 2007
- μ- and κ-Opioids Induce the Differentiation of Embryonic Stem Cells to Neural ProgenitorsPublished by Elsevier BV ,2006
- NEURAL MECHANISMS OF ADDICTION: The Role of Reward-Related Learning and MemoryAnnual Review of Neuroscience, 2006
- Role of Noradrenergic Signaling by the Nucleus Tractus Solitarius in Mediating Opiate RewardScience, 2006
- The effect of a systemically active ORL-1 agonist, Ro 64-6198, on the acquisition, expression, extinction, and reinstatement of morphine conditioned place preferenceNeuropharmacology, 2005
- Dopamine, learning and motivationNature Reviews Neuroscience, 2004
- The delta agonists DPDPE and deltorphin II recruit predominantly mu receptors to produce thermal analgesia: a parallel study of mu, delta and combinatorial opioid receptor knockout miceEuropean Journal of Neuroscience, 2004
- Descending control of painProgress in Neurobiology, 2002
- Central mechanisms of pain modulationCurrent Opinion in Neurobiology, 1999
- The neural basis of drug craving: An incentive-sensitization theory of addictionBrain Research Reviews, 1993