Expression of mu opioid receptor in dorsal diencephalic conduction system: New insights for the medial habenula

Abstract

The habenular complex, encompassing medial (MHb) and lateral (LHb) divisions, is a highly conserved epithalamic structure involved in the dorsal diencephalic conduction system (DDC). These brain nuclei regulate information flow between the limbic forebrain and the mid- and hindbrain, integrating cognitive with emotional and sensory processes. The MHb is also one of the strongest expression sites for mu opioid receptors (MORs), which mediate analgesic and rewarding properties of opiates. At present however, anatomical distribution and function of these receptors have been poorly studied in MHb pathways. Here we took advantage of a newly generated MOR-mcherry knock-in mouse line to characterize MOR expression sites in the DDC. MOR-mcherry fluorescent signal is weak in the lateral habenula, but strong expression is visible in the medial habenula, fasciculus retroflexus and interpeduncular nucleus (IPN), indicating that MOR is mainly present in the MHb-IPN pathway. MOR-mcherry cell bodies are detected both in basolateral and apical parts of MHb, where the receptor co-localizes with cholinergic and Substance P (SP) neurons, respectively, representing two main MHb neuronal populations. MOR-mcherry is expressed in most MHb-SP neurons, and is present in only a subpopulation of MHb-cholinergic neurons. Intense diffuse fluorescence detected in lateral and rostral parts of the IPN further suggests that MOR-mcherry is transported to terminals of these SP and cholinergic neurons. Finally, MOR-mcherry is present in septal regions projecting to the MHb, and in neurons of the central and intermediate IPN. Together, this study describes MOR expression in several compartments of the MHb-IPN circuitry. The remarkably high MOR density in the MHb-IPN pathway suggests that these receptors are in a unique position to mediate analgesic, autonomic and reward responses.

Deletion of the mu opioid receptor gene in mice reshapes the reward–aversion connectome

“…3A). Thus, major changes of connectivity strength for the two nodes demonstrate concerted perturbation of the entire dorsal diencephalic conduction pathway (32) (3,33). We found only subtle modifications of structural scaffolding (Fig.…”

Translating the Habenula—From Rodents to Humans

“…LHb neurons are also characterized by heterogeneous expression of monoaminergic receptors across sub-nuclei, mainly dopaminergic D2 receptors and serotonin 5-HT2C receptors (19). Similarly, MHb contains mainly glutamatergic neurons distributed into three phenotypically distinct populations, i. e. neurons expressing glutamate alone or co-expressing either substance P or acetylcholine (19, 20). …”

“…Mu opioid receptors are strongly expressed in the habenular, mainly within MHb (20), and likely interact with cholinergic transmission. In rats, blockade of α3β4 nicotinic receptors in MHb and IPN attenuates sensitization of the dopamine response to repeated morphine administration, and chronic exposure to morphine enhances cholinergic signaling in the MHb (62).…”

Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation

“…However, the role of this projection in opioid aversion has also not been defined. The lateral habenula, an important site of aversion, reduces striatal DA levels by inhibiting VTA dopamine neurons via projections to GABAergic neurons in the RMTg [99–101]. While this lateral habenula circuitry is an important component of the negative prediction error and negative affect [43], the role of this pathway in the negative affect following chronic opioids is unknown.…”

“…Excitatory MSNs are characterized by expression of dopamine D1 receptors, GABA, dynorphin, and substance P, whereas inhibitory MSNs are characterized by the expression of dopamine D2, GABA, enkephalin, and adenosine A2a receptors. The NAc also receives excitatory (glutamatergic) input from the basolateral amygdala, ventral hippocampus, and prefrontal cortex that drives drug reinforcement, whereas input from the paraventricular nucleus of the thalamus can drive reward or aversion associated with withdrawal [78,101]. Chronic morphine is known to increase or decrease long-term potentiation (LTP) and long-term depression (LTD) of some of these glutamatergic inputs, and this may depend on the method of morphine administration (contingent versus non-contingent) [75].…”