Stress transduction in the adrenal medulla

Along with the myriad of sympathetic nerves which are finely distributed throughout the body, there is also a cluster of specialized sympathetic neuroendocrine cells which comprise the adrenal medulla. Unlike the mesodermal cortex which surrounds it, the adrenal medulla is embryologically related to the same neural crest tissue that develops into the post-ganglionic sympathetic neurons, but through the course of development take on a very different character.

Figure 1: Histology of the adrenal gland. The mesodermal adrenal cortex

surrounding the medulla is divided into three functional and histologic layers.

The adrenal medulla consists of a homogenous population of adrenal chromaffin

cells, which together comprise a specialized type of sympathetic ganglion.

Part 1: Chromaffin Cells

The effector cells of the adrenal medulla are the chromaffin cells.

Unlike the typical sympathetic neurons, the chromaffin cells do not have dendritic processes and do not form synapses on target organs. Rather, when they are appropriately stimulated they release the contents of their vesicles directly into the bloodstream where they exert an endocrine, rather than paracrine effect.

Figure 2: Chromaffin cells of the adrenal medulla. These cells, were they to

undergo malignant transformation, are the precursor cells of pheochromocytoma

or sympathetic paraganglioma.

As a form of specialized sympathetic ganglion, the adrenal medulla receives its innervation directly from the cholinergic preganglionic fibers. These fibers stem from the cervical sympathetic chain at the level of T5-T8 and comprise the greater splanchnic nerve. There are also postganglionic sympathetic nerves stemming from the celiac ganglion which penetrate the adrenal gland and innervate the capillary bed, but do not interact with the chromaffin cells themselves.

Part 2: The Adrenal Synapse

The presynaptic terminal of the splanchnic nerve fiber contains both small clear vesicles (SCVs) and as well as large dense-core granules (LDCGs). Much as in other sympathetic nerves, the small clear vesicles contain acetylcholine, which is the primary neurotransmitter of the preganglionic sympathetic nerves. The large dense core granules contain a neuropeptide called PACAP (pituitary adenylate cyclase activating peptide).

As with the rest of the sympathetic nerves, the acetylcholine-containing SCVs are released proportionally to the firing frequency of the splanchnic nerve. The large dense core vesicles, on the other hand, require a profoundly increased calcium concentration for exocytosis. In order to create this large calcium influx, extremely high firing frequency is required. In this way the splanchnic nerves have both a graded response expressed in acetycholine release as well as an all-or-nothing response expressed in PACAP release. 

Figure 3: The anatomy of the splanchnic nerve and associated sympathetic fibers innervating the adrenal gland. From Netters.

Part 3: Stress Transduction

Given the physiology of the presynaptic terminal and its distinction between regular firing and high-intensity firing, it is unsurprising that the adrenal medulla has distinct ways of responding to the two firing modes in terms of its response. Low frequency firing and acetylcholine release are sufficient to produce a graded response of norepinephrine release from the chromaffin cells. Acetylcholine release does also produce a small amount of epinephrine release as well, however, due to receptor desensitization and vesicle depletion acetylcholine alone is unable to produce a robust epinephrine response, instead only producing limited transient release. 

Figure 4: Physiology of the splanchnic nerve terminal. Low firing frequency

results in release of acetylcholine from SCVs only, whereas high firing frequency

is sufficient to cause release of PACAP from LDCGs. From Smith and Eiden

(2012).

High firing frequency and PACAP release, on the other hand, produces a complex set of responses within the chromaffin cell which result in robust and sustained epinephrine secretion. This response begins with direct PACAP mediated exocytosis of epinephrine, which unlike the acetylcholine-mediated response is non-desensitizing as well as action potential independent. This response is followed by induction of multiple enzymes including tyrosine hydroxylase and PNMT which are key members of the epinephrine synthetic pathway and are required for maintained epinephrine secretion. In other words, high frequency splanchnic nerve firing represents the sympathoadrenal stress response and is required for high volume endocrine secretion of epinephrine.

Part 4: Glucocorticoids are necessary for the medullary response.

Figure 5: Activation of the adrenal cortex. From Herman et al (2016)

One final component of the adrenal medullary stress response is that, while it requires sympathetic activation in the form of high frequency splanchnic nerve firing, it also requires concurrent stimulation by the HPA axis in the form of cortisol secretion. As was discussed earlier, the adrenal cortex and adrenal medulla share very little in terms of embryology. They also differ wildly in terms of overall structure, as the adrenal cortex is a hormonal system regulated by pituitary ACTH while the adrenal medulla is part of a neural system regulated by splanchnic sympathetic tone. However, inasmuch as they comprise two arms of a physiologic stress response they have much in common and even at times have overlapping functional roles.

Much like the sympathetic response, the adrenal cortical response is initiated in the paraventricular nucleus of the hypothalamus (PVN). Also similar to the sympathetic response, activation of the CRH-secreting neurons can be activated through peripheral mechanisms, largely stimulated by the same pre-sympathetic pathways that activated the CVLM for sympathetic tone, as well as central mechanisms through the limbic system for anticipatory or psychologic stress responses. In either circumstance, activation of the PVN in this manner results in release of CRH into the hypophyseal-pituitary circulation, which results in ACTH secretion by the anterior pituitary gland. Once in systemic circulation, the ACTH activates receptors in the adrenal cortex which result in production of glucocorticoids. These glucocorticoids then drain through the corticomedullary circulation where they result in transcriptional activation of PNMT.

In patients with adrenal insufficiency the resulting low corticosteroid state prevents adequate transcription of PNMT and eliminates the serum epinephrine response to stress. In experimental models of PACAP depletion or knockout basal PNMT and epinephrine secretion still exist, but are part of a low-volume easily depleted response in the absence of an autonomic stress response.

References: 

Smith, Corey B., and Lee E. Eiden. "Is PACAP the major neurotransmitter for stress transduction at the adrenomedullary synapse?." Journal of Molecular Neuroscience 48.2 (2012): 403-412.

Wolf, Kyle, et al. "Spatial and activity‐dependent catecholamine release in rat adrenal medulla under native neuronal stimulation." Physiological reports 4.17 (2016): e12898.

Herman et al. "Regulation of the hypothalamic-pituitary-adrenocortical stress response". Compr Physiol. ; 6(2): 603–621 (2016). doi:10.1002/cphy.c150015