Volume transmission of beta-endorphin via the cerebrospinal fluid; a review

Abstract

There is increasing evidence that non-synaptic communication by volume transmission in the flowing CSF plays an important role in neural mechanisms, especially for extending the duration of behavioral effects. In the present review, we explore the mechanisms involved in the behavioral and physiological effects of β-endorphin (β-END), especially those involving the cerebrospinal fluid (CSF), as a message transport system to reach distant brain areas. The major source of β-END are the pro-opio-melano-cortin (POMC) neurons, located in the arcuate hypothalamic nucleus (ARH), bordering the 3rd ventricle. In addition, numerous varicose β-END-immunoreactive fibers are situated close to the ventricular surfaces. In the present paper we surveyed the evidence that volume transmission via the CSF can be considered as an option for messages to reach remote brain areas. Some of the points discussed in the present review are: release mechanisms of β-END, independence of peripheral versus central levels, central β-END migration over considerable distances, behavioral effects of β-END depend on location of ventricular administration, and abundance of mu and delta opioid receptors in the periventricular regions of the brain.

Figure 1

Diagram showing the opiocortin projections from the arcuate nucleus of the hypothalamus. The arcuate nucleus (ARH) contains most β-END cell bodies and is located in the mediobasal hypothalamus, at both sides of the 3^rd ventricle (not shown). Extensive opiocortin projections arise from the ARH and extend in rostral, cortical, hypothalamic and caudal brainstem directions. The most caudal projections extend into the dorsal vagal complex (DVC), comprising the area postrema, the dorsal vagal nucleus and the nucleus of the solitary tract (NTS). Limbic regions predominate as target areas for the ARH projections. In the caudal brainstem, in the NTS itself, another group of β-END cells has been detected. Their opiocortin fibers project mainly to brainstem areas as well as down the spinal cord. A number of brainstem areas, involved in numerous autonomic functions, receive a double innervation from both the ARH and the NTS: locus coeruleus (LC), the parabrachial region (PB) and several raphe nuclei (RN). Abbreviations: NAc: nucleus accumbens; Olf. Tub: olfactory tubercle; DBB: diagonal band nuclei; POA: preoptic area; PVH: paraventricular hypothalamic nucleus; SON: supraoptic hypothalamic nucleus; pv: periventricular thalamus; Pit: pituitary; VTA: ventral tegmental area.

Figure 2

Diagram showing the flow of CSF in the volume transmission of β-endorphin. The main release site for β-END is the arcuate nucleus of the hypothalamus. The additional hindbrain site is located just ventral to no 6. The flow of the CSF (red arrows) traverses the aqueduct (AQ) to penetrate the mesencephalic periaqueductal gray before reaching the 4^th ventricle (V4), and along the ‘vagal-complex’ region. Both regions are important target areas for the flowing β-END. After leaving the ventricular system, the flowing CSF may affect superficial brain regions in the brainstem, hypothalamus and olfactory regions. A considerable part of the CSF and its contents eventually leaves the cranial cavity along the olfactory nerves penetrating the cribriform plate. The telencephalon is indicated in pink colours. The diencephalon (‘interbrain’) is coloured yellow, similar to the brainstem structures and the cerebellum is blue. Black structures show the location of fiber systems which cross the midline. Other symbols: numbers 1–6: circumventricular organs; cc: central canal of spinal cord; IVF: interventricular foramen, connecting the lateral and the 3^rd ventricles; V3: 3^rd ventricle. (The original figure was kindly provided by L.W. Swanson).