The Influence of Morphine on Cerebral 5-HT_2A Availability in Dogs: a SPECT Study

Abstract

The opioid and serotonergic systems are closely involved in pain processing and mood disorders. The aim of this study was to assess the influence of systemic morphine on cerebral serotonin 2A receptor (5-HT 2A ) binding in dogs using SPECT with the 5-HT 2A radioligand 123 I-5I-R91150. Methods: 5-HT 2A binding was estimated with and without morphine pretreatment in 8 dogs. The 5-HT 2A binding indices in the frontal, parietal, temporal, and occipital cortex and in the subcortical region were obtained by semiquantification. Results: A significantly decreased 5-HT 2A binding index was found in the morphine group for the right (morphine, 1.41 6 0.06; control, 1.52 6 0.10) and left (morphine, 1.44 6 0.08; control, 1.55 6 0.11) frontal cortices, with P 5 0.012 and P 5 0.040, respectively. No significant differences were noted for the other regions. Conclusion: Morphine decreased the frontocortical 5-HT 2A availability, confirming an interaction between the 5-HTergic and the opioid systems. Whether this interaction is caused by decreased receptor density due to direct internalization or is the result of indirect actions, such as increased endogenous serotonin release, remains to be elucidated.Key Words: serotonin (5-HT); 5-HT 2A ; morphine; SPECT; frontal cortex Nucl Med 2012; 53:1969 53: -1973 53: DOI: 10.2967 It is well documented that there is a close interaction between the brain opioid and serotonin (5-hydroxytryptamine [5-HT]) neurotransmitter systems (1-3). Activation of the m-opioid receptor system leads to 5-HTergic changes, including increased release of synaptic 5-HT, as was shown in several brain regions and in the spinal cord in various in vivo microdialysis studies (1,2). Furthermore, pharmacologic and behavioral studies pointed out that the 5-HTergic system is implicated in spinal pain transmission, modulation, and control and particularly in the mediation of opioid analgesia (3,4). Morphine-induced analgesia is thought to rely in part on the indirect activation of descending inhibitory 5-HTergic pathways (3). Consequently, antidepressants that inhibit 5-HT reuptake, such as fluvoxamine and fluoxetine, are also known to have analgesic properties, especially in chronic pain states (5,6). JBeside its role in pain modulation (7-9), 5-HT 2A receptor (5-HT 2A ) gained interest over the last few decades due to its involvement in several neurologic disorders in humans, including anxiety (10), depression (11), schizophrenia (12), and obsessive-compulsive disorder (13). More specifically, atypical antipsychotic drugs acting as 5-HT 2A antagonists and inverse agonists were seen to be effective in reducing the symptoms of these diseases (10,14). Because the opioid system has been shown to be involved in several of these mood disorders as well (15), the interaction between m-opioid receptors and 5-HT 2A at an emotional or cognitive level gained interest, partly with regard to common opioid side effects such as tolerance and addiction that are thought to have a 5-HTergic component as well. Consequently, several in v...

5-HT2A Serotonin Receptor Density in Adult Male Rats’ Hippocampus after Morphine-based Conditioned Place Preference

“…Also in recent years, some researchers have studied the influence of morphine on cerebral 5-HT 2A receptor availability in dogs; their results indicated that a single dose of morphine decreased 5-HT 2A receptor binding index in the frontal cortex ( Adriaens et al, 2012 ), but prolonged morphine exposure lowered the 5-HT 2A receptor binding index in frontal, temporal, and parietal cortex as well as subcortical region ( Adriaens et al, 2014 ). These data provide further evidence for the interaction between the opioid and serotonergic system and encourages further research on the possible beneficial effects of opioids in the treatment of mood disorders ( Adriaens et al, 2014 ).…”

“…These data provide further evidence for the interaction between the opioid and serotonergic system and encourages further research on the possible beneficial effects of opioids in the treatment of mood disorders ( Adriaens et al, 2014 ). Apparently, the influence of morphine on the availability of 5-HT 2A receptor might be different in the presence of acute noxious stimulation ( Adriaens et al, 2012 ).…”

“…More research is necessary to investigate the role of this receptor in place conditioning, which may contribute to a better understanding of its potential role in the conditioned effects of drugs abuse ( Hayes & Greenshaw, 2011 ). Since both opioids (like morphine) and 5-HT 2A receptors appear to be involved in similar biological processes ( Adriaens et al, 2012 ; Adriaens et al, 2014 ), the aim of the present study was to assess the influences of morphine and CPP on the density of 5-HT 2A receptor in neurons of rat hippocampal formation.…”

The role of serotonin 5-HT2A receptors in memory and cognition

“…That is, if the problem of drug abuse is approached as a mental disorder of memory, then pharmacological manipulations that facilitate extinction may hold therapeutic utility for treating drug abuse. Drug exposure alters the expression and function of 5-HT 2A R, for example morphine decreases frontocortical 5-HT 2A R binding affinity in dogs ( Adriaens et al, 2012 ). 5-HT 2 Rs are up-regulated in amygdala, midbrain, pons, and medulla of morphine-tolerant and -dependent rats, but not in morphine-abstinent rats ( Gulati and Bhargava, 1989 ).…”

The Effect of Morphine on Regional Cerebral Blood Flow Measured by 99mTc-ECD SPECT in Dogs

“…This could possibly suggest that morphine exerts its effect at a different level at this time point. On the one hand, changes in the serotonergic neuroreceptor system have been found in a previous study, possibly indicating that the downstream effects of morphine are more important for its effect [34] . On the other hand, a peripheral action (spinal or at the periphery) rather than a supraspinal action could be responsible for the effect of morphine at a later time point.…”