Endogenous opioids in the olfactory tubercle and their roles in olfaction and quality of life

Abstract

Olfactory dysfunctions decrease daily quality of life (QOL) in part by reducing the pleasure of eating. Olfaction plays an essential role in flavor sensation and palatability. The decreased QOL due to olfactory dysfunction is speculated to result from abnormal neural activities in the olfactory and limbic areas of the brain, as well as peripheral odorant receptor dysfunctions. However, the specific underlying neurobiological mechanisms remain unclear. As the olfactory tubercle (OT) is one of the brain's regions with high expression of endogenous opioids, we hypothesize that the mechanism underlying the decrease in QOL due to olfactory dysfunction involves the reduction of neural activity in the OT and subsequent endogenous opioid release in specialized subregions. In this review, we provide an overview and recent updates on the OT, the endogenous opioid system, and the pleasure systems in the brain and then discuss our hypothesis. To facilitate the effective treatment of olfactory dysfunctions and decreased QOL, elucidation of the neurobiological mechanisms underlying the pleasure of eating through flavor sensation is crucial.

Keywords: brain reward system; dopamine; olfactory tubercle; opioid; preproenkephalin; prodynorphin; quality of life.

Figure 1

Pdyn-Penk co-expressing D1 neurons in the mouse OT. (A) Single probe in situ hybridization for Pdyn, Penk, Drd1, and Drd2. The pictures show coronal sections of the anterior OT and NAc (approximately at Bregma +1.94 mm). Regions delineated by red lines are a cluster of Pdyn-Penk-Drd1 co-expressing cells. Drd2 signals were not observed in the cluster. Adjacent sections from one mouse were used for the four images. (B) Triple fluorescence in situ hybridization for Pdyn, Penk, and Drd1 in the anteromedial OT. White arrowheads indicate the colocalization of Pdyn-Penk-Drd1 mRNAs. D, dorsal; V, ventral; M, medial; L, lateral. Figures are modified from Maegawa et al. (2022).

Figure 2

A hypothetical model of OT opioid-mediated QOL and its impairment due olfactory dysfunctions. In a healthy condition, food-related olfactory inputs, including food odorants via the retronasal pathway, are conveyed to the anteromedial OT, where Pdyn-expressing and Pdyn-Penk-coexpressing D1 neurons are activated. Subsequently, opioid peptides are released from D1 neurons in the anteromedial OT, resulting in hedonic pleasure sensation. In some cases of olfactory dysfunctions, the retronasal airflow is blocked, inhibiting the transmission of the olfactory inputs to the anteromedial OT. This, in turn, impairs neural activation and opioid release of the anteromedial OT, which reduces the sensation of pleasure. Red circles, Pdyn-expressing D1 neurons; green circles, Pdyn-Penk-coexpressing D1 neurons; blue circles, Penk-expressing neurons D2. OTam, anteromedial olfactory tubercle; OTal, anterolateral olfactory tubercle; NAc, nucleus accumbens; VP, ventral pallidum; D, dorsal; V, ventral; M, medial; L, lateral. Stereotax atlas from Franklin and Paxinos (2008).