Parasympathetic Fibers Research Articles

Blood-brain barrier opened by stimulation of the parasympathetic sphenopalatine ganglion: a new method for macromolecule delivery to the brain.

Drug delivery across the blood-brain barrier remains a significant challenge. Based on earlier findings, the authors hypothesized that parasympathetic innervation of the brain vasculature could be used to augment drug delivery to the brain. Using a craniotomy-cerebrospinal fluid superfusate paradigm in rats with an intravenous injection of tracer the authors demonstrated that stimulation of the postganglionic parasympathetic fibers of the sphenopalatine ganglion (SPG) increased the concentration of fluorescein isothiocyanate-dextran (4-250 kD) in the superfusate by two- to sixfold. A histological examination indicated the presence of dextran in the parenchyma. In another experiment the amount of Evans blue dye in the brain following SPG activation was similarly significantly elevated. The chemotherapeutic agents anti-HER2 monoclonal antibody and etoposide were also delivered to the brain and reached therapeutic concentrations. Brain homeostasis was not disturbed by this procedure; a measurement of nicotinamide adenine dinucleotide reduction did not show a decrease in the tissue metabolic state and brain water content did not increase significantly. Sphenopalatine ganglion activation demonstrates a promising potential for clinical use in the delivery of small and large molecules to the brain.

Pituitary adenylate cyclase-activating polypeptide enhances the hyperpolarization-activated nonselective cationic conductance, Ih, in dissociated guinea pig intracardiac neurons

Pituitary adenylate cyclase-activating polypeptide (PACAP) peptides, which are co-localized with acetylcholine in preganglionic parasympathetic fibers innervating guinea pig intracardiac ganglia, depolarize and increase excitability of intracardiac neurons. Perforated patch whole cell recordings were used to test whether PACAP27-enhanced activation of Ih contributed to the increase in excitability. In current clamp, 100 nM PACAP27 increased rectification during 500-ms hyperpolarizations and increased the number of anodal break action potentials (APs). PACAP27 also increased the number of APs produced by 500-ms depolarizing currents. In voltage clamp, the effects of 100 nM PACAP27 were determined during hyperpolarizing steps from −50 mV to voltages between −60 and −120 mV. PACAP27 increased the amplitude and rate of activation of Ih. PACAP27 shifted the voltage dependence of activation of Ih by 6.6 mV. The effect of PACAP27 was eliminated by pretreatment with the Ih inhibitor ZD7288 (100 μM). The adenylyl cyclase activator forskolin (10 μM) produced a similar shift in the voltage dependence of Ih activation. We conclude that PACAP27 enhances Ih by shifting the voltage dependence of activation and propose that this effect is mediated primarily by PAC1 receptor activation of adenylyl cyclase and generation of cAMP. Furthermore, we propose that the peptide-enhanced Ih contributes to the PACAP27-induced increase in membrane excitability.

Neural control of the respiratory nasal mucosa

Respiratory nasal mucosa fulfils the function of pretreating the inspired air. The periodic nasal cycle and pathologic functional disturbances of the endonasal tissue influence the nasal passages. The secretion of the seromucous glands and extravasation from the blood vessels are essential for mucocilliary transport. These physiological mechanisms are partially controlled by neural regulation. Besides classic neurotransmitter neuropeptides such as VIP, CGRP, SP and NPY, nitric oxide also shares this role. A network of sensory, sympathetic and parasympathetic nerve fibres protects the respiratory mucous membranes from external and internal irritation. In addition, blood vessels and glands are influenced by endothelial and humoral factors. For the different types of rhinitis, sensory neuropeptides and inflammatory mediators take part in the pathomechanisms and can lead to a so called neurogenic inflammation of the nasal mucosa.

Role of vasoactive intestinal peptide and inflammatory mediators in enteric neuronal plasticity.

Complex circuits involving both local intrinsic neurones (i.e. enteric nervous system; ENS) and extrinsic neurones achieve nervous control of digestive functions. The ENS is comprised of many functionally different types of neurons: sensory neurons, interneurons and secreto-motor neurons. Each neuronal population is required to manifest local reflex behavior and is central to the regulation of both motor and secretory activities. It must be emphasized, however, that not only muscle and secretory cells but also other intestinal cells are targeted by enteric neurones, i.e. endocrine cells, interstitial cells of Cajal, immune cells, blood vessels and enteric glia. In addition to the ENS the gastrointestinal tract receives an extrinsic innervation by sympathetic, parasympathetic and sensory fibres. Neuronal projections from the intestine to prevertebral ganglia also exist. Taken together, the picture of a complex nervous regulation of digestive functions highly integrated with the central nervous system and the rest of the autonomic nervous system has emerged. The ENS is adaptive and plastic, but also vulnerable, system and ENS disturbances may be of pathogenic importance in functional bowel disease. In particular the interplay between the enteric neurones and the immune cells is suggested to be of crucial importance. The review discusses possible roles of the mediators vasoactive intestinal peptide (VIP) and prostanoids in ENS plasticity in response to injury and inflammation.

The effects of vagal stimulation on laryngeal vascular resistance and intraluminal pressure in the dog.

In anaesthetized dogs (sodium pentobarbitone 30 mg/kg, i.v.) laryngeal vascular resistance was measured by unilateral perfusion at constant flow of the branch of the cranial superior thyroid artery that supplies the larynx. Arterial perfusion was at constant flow and inflow pressure was divided by flow to give laryngeal vascular resistance (R(LV)). Intraluminal laryngeal pressure (P(L)) and systemic arterial blood pressure (BP) were also measured. Stimulation (20 V, 20 Hz, 0.2 milliseconds) of the central end of cervical vagus caused an increase in R(LV) (+22.9+/-6.1%) and a decrease in P(L) (-12.1+/-4.4%). Stimulation (10 V, 10 Hz, 0.2 milliseconds) of the central end of the recurrent laryngeal nerve (RLN) reduced RLV (-3.4+/-0.8%) and P(L) (-7.5+/-4.1%). Stimulation of the peripheral end of the RLN decreased R(LV) (-7.1+/-1.9%) and increased PL (+21.6+/-7.7%). Stimulation of the central end of the superior laryngeal nerve (SLN) increased R(LV) (+17.9+/-3.2%) and P(L) (+59.8+/-2.7%), whereas stimulation of the peripheral end of the SLN decreased R(LV) (-4.8+/-1.6%) and P(L) (-4.1+/-2.4%). After treatment with alpha-adrenoreceptor antagonist phentolamine (0.5 mg/kg, i.v.), stimulation of the central end of cervical vagus nerve reduced R(LV) by 25% and decreased BP. Phentolamine caused a decrease in BP and reduced the magnitude of increase in R(LV) in response to stimulation of central end of SLN. After atropine sulphate (0.5-2.0 mg/kg, i.v.), the stimulation of both central and peripheral ends of RLN reduced R(LV). The decrease in R(LV) during stimulation of peripheral end of SLN was reduced by atropine. Thereafter, pancuronium bromide (0.06-0.1 mg/kg, i.v.) was given and dogs were artifically ventilated. After paralyzed, stimulation of the central end of the SLN decreased R(LV) (+26.0+/-4.5%) but produced no change in P(L), It is concluded that parasympathetic motor fibers in the RLN and SLN are effective for the laryngeal vascularity and non-adrenergic system may be responsible for laryngeal vasoconstriction. laryngeal vasculature; vagal stimulation; phentolamine; atropine

Distribution of pterygopalatine ganglion efferents to the lacrimal gland in man

To trace the path taken by the putative postganglionic secretomotor fibres to the lacrimal gland the contents of the orbital and pterygopalatine fossa were removed whole, cut coronally into slabs and embedded in resin. Thin sections were cut at varying intervals to reconstruct the pathway taken. One group of rami orbitales issuing from the pterygopalatine ganglion passed dorsally adjacent to the lateral wall of the orbit, joined the retro-orbital plexus at the apex, and 5–10 rami lacrimales advanced from the plexus to enter the gland. An accessory ophthalmic artery, a branch of the middle meningeal artery, entered the orbit through the superior fissure orbital joining the ophthalmic or lacrimal artery. Perivascular nerves of the artery continued to the gland as supplementary rami lacrimales and in some orbits others served the vasculature of the eye and orbit. The nerves are presumably derived from the middle meningeal supply and may include otic parasympathetic fibres. The route taken by parasympathetic nerves serving the human lacrimal gland is demonstrated here for the first time and apart from the perivascular meningeal artery source, it is similar to that described in monkeys. The traditional assumption that secretomotor nerves pass to the gland via the zygomatic and lacrimal nerves is therefore unlikely and clinical measures to reduce lacrimation based on that assumption and involving severance of ophthalmic branches is not indicated.

An unusual site for an intraoral schwannoma: a case report

Schwannomas are benign tumors that are rarely found in the oral cavity. We presented a schwannoma arising from the parasympathetic fibers of the lingual nerve, which is the first in the literature to our knowledge. Its borders in computerized tomography are not well defined despite the contrast medium.

Comparative histological and biometric study of the coronary, radial and left internal thoracic arteries

In an attempt to elucidate the causes of occlusion of radial arteries used for coronary artery bypass grafts and to improve the results of these procedures, we studied the biometry and histology of the coronary, radial and left internal thoracic arteries. These arteries were harvested from 20 cadavers (13 males, 7 females). The specimens were calibrated to the various bypass graft sites using coronary calibrators, and were then submitted to histological examination to determine the structure and innervation of the vessel wall. No correlation was observed between the internal calibers of these various arteries, with the exception of the anterior interventricular and right coronary arteries. Intimal changes and the presence of atheromatous plaque were observed in coronary and radial arteries, but never in the internal thoracic artery. Like the coronary arteries and their branches, the radial artery is a muscular artery. Aging of muscular arteries results in thickening of the intima, which becomes fibrotic due to migration of myocytes from the media and duplication of the internal elastic lamina. The media becomes fibrous, hypertrophic or atrophic. The walls of the radial and coronary arteries contain several adventitial nerves (sympathetic and parasympathetic nerve fibers), but these nerve fibers were not observed in the wall of the left internal thoracic artery. In contrast, the internal thoracic artery, like the aorta, is an elastic artery. Aging of elastic arteries is first observed between the ages of 20 and 29 years and is characterized by loss of one or several elastic laminae of the media and more marked intimal thickening, over a variable length. Even if a radial artery's caliber is similar to that of the coronary artery, histological evolution and graft patency depend on its muscular identity.

Distribution of vasoactive intestinal polypeptide in the rat heart: effect of guanethidine and capsaicin

Vasoactive intestinal polypeptide (VIP) is believed to coexist with acetylcholine in postganglionic parasympathetic neurones. However, the presence of VIP in extrinsic nerves and/or other types of intrinsic cardiac neurones has not been excluded. The aim of our study was to examine the distribution and origin of VIP-ergic innervation in the rat heart atria using immunocytochemistry and radioimmunoassay (RIA) combined with two types of denervation: sympathectomy, which was produced by guanethidine treatment and sensory denervation achieved by capsaicin administration. In whole-mount preparations of the intact atria, VIP-immunoreactive (IR) nerve fibres and ganglionic cells were found, the latter being much more numerous in the left atria (LA) than in the right ones. Some of VIP-IR nerve fibres forming bundles appeared to be extrinsic in origin. VIP-IR concentrations determined by RIA in the intact rats were significantly higher in the LA than in the right ones (p < 0.01). However, no changes in VIP-IR levels were found in either atrium after both guanethidine and capsaicin treatment protocols, thus indicating that VIP-immunoreactivity is not associated with either sympathetic or sensory innervation. In conclusion, the ganglionated plexus of the rat atria may comprise at least 3 different neuronal populations expressing VIP-positivity: 1. extrinsic preganglionic parasympathetic fibres, 2. intrinsic postganglionic parasympathetic neurones and 3. intrinsic local circuit neurones that do not express a cholinergic phenotype.

Genetic association studies: What are they teaching clinicians?

Genetic association studies: What are they teaching clinicians?

Musings on the wanderer: what's new in our understanding of vago-vagal reflex? IV. Current concepts of vagal efferent projections to the gut.

Vagal efferents, consisting of distinct lower motor and preganglionic parasympathetic fibers, constitute the motor limb of vagally mediated reflexes. Arising from the nucleus ambiguus, vagal lower motor neurons (LMN) mediate reflexes involving striated muscles of the orad gut. LMNs provide cholinergic innervation to motor end plates that are inhibited by myenteric nitrergic neurons. Preganglionic neurons from the dorsal motor nucleus implement parasympathetic motor and secretory functions. Cholinergic preganglionic neurons form parallel inhibitory and excitatory vagal pathways to smooth muscle viscera and stimulate postganglionic neurons via nicotinic and muscarinic receptors. In turn, the postganglionic inhibitory neurons release ATP, VIP, and NO, whereas the excitatory neurons release ACh and substance P. Vagal motor effects are dependent on the viscera's intrinsic motor activity and the interaction between the inhibitory and excitatory vagal influences. These interactions help to explain the physiology of esophageal peristalsis, gastric motility, lower esophageal sphincter, and pyloric sphincter. Vagal secretory pathways are predominantly excitatory and involve ACh and VIP as the postganglionic excitatory neurotransmitters. Vagal effects on secretory functions are exerted either directly or via release of local mediators or circulating hormones.

Centrally mediated reflex vasodilation in the gingiva induced by painful tooth‐pulp stimulation in sympathectomized human subjects

This study was designed to determine whether painful electrical stimulation of the tooth pulp induces centrally mediated reflex vasomotor changes in human gingiva and whether the sympathetic nervous system is involved in the vasomotor responses. Dynamic changes in maxillary gingival blood flow (GBF) following painful electrical stimulation of the mandibular lateral incisor were investigated, by means of laser-Doppler flowmetry, in both healthy volunteers and patients undergoing sympathetic blockade for hyperhidrosis. Increases in GBF were observed in both healthy volunteers and patients on the ipsilateral side without an increase in systemic blood pressure, but the evoked GBF increase disappeared when pain sensation was abolished by local anesthetization with 2% xylocaine solution. The vasodilator responses did not differ in amplitude between before and after the sympathectomy. These results suggest that painful tooth stimulation evokes centrally mediated reflex vasodilation, presumably via parasympathetic efferent fibers, in the human gingiva and that sympathetic vasomotor mechanisms are not involved in these responses.

Autonomic dysfunction in peripheral nerve disease.

Autonomic neuropathies are inherited or acquired neuropathies in which autonomic nerve fibers are selectively or disproportionately affected. Generally, sympathetic and parasympathetic fibers are both affected but there are exceptions. Acquired cases can be autoimmune; due to diabetes, amyloidosis, drugs, or toxins; or idiopathic. Autoimmune autonomic neuropathy is often subacute, sometimes associated with a neoplasm, and associated with high titers of antibody to ganglionic nicotinic acetylcholine receptor in about half of the severe cases. The molecular basis of inherited autonomic neuropathies is better known, including recent identification of the loci and genes of hereditary sensory and autonomic neuropathies types I, III, and IV. The inherited amyloid neuropathies are due to mutations of three proteins: transthyretin, apolipoprotein A1, and gelsolin. Non-invasive autonomic testing complements clinical and electrophysiological characterization of the autonomic neuropathies.

Investigation of the Localization of Nerves in the Uterosacral Ligament: Determination of the Optimal Site for Uterosacral Nerve Ablation

We select surgical treatment for cases for which severe dysmenorrhea persists following medical treatment. Many reports have described the use of neurectomies by cutting off pain conducting nerve pathways using laparoscopic surgery. Laparoscopic uterosacral nerve ablation (LUNA) has been associated with a high success rate for pain control, but there are few reports of anatomical studies in the uterosacral ligament. Using an immunohistochemical method, we examined the number and types of nerve fiber bundles in the uterosacral ligaments and its surrounding tissue in cadavers. The greatest number of nerve fiber bundles was found at a distance of 16.5–33 mm and at a depth of 3–15 mm distal to the site of attachment of the uterosacral ligament to the uterine cervix. Furthermore, there were many more sympathetic and parasympathetic nerve fiber bundles than sensory ones in the uterosacral ligament and its surrounding tissue. These results show the appropriate site of transection of uterosacral ligaments when performing LUNA.

Quantitative immunohistochemical investigation of the intrinsic vasodilator innervation of the guinea pig lingual artery

The vasculature of the guinea pig tongue is supplied by parasympathetic vasodilator nerve fibres of intrinsic origin. Here, we investigated first to what extent neuropeptides and the synthesizing enzymes of NO, CO and acetylcholine are contained and colocalized within periarterial lingual vasodilator axons of intrinsic origin. Then it was determined whether perivascular innervation by these fibre types changes with vascular diameter, in particular in comparison with the sensory substance P (SP)-positive and sympathetic noradrenergic vascular innervation. To this end, single, double and triple labelling histochemical techniques were performed on control tongues and tongues kept in short-term organotypic culture to induce degeneration of extrinsically originating nerve fibres. Cell bodies of intrinsic microganglia and their periarterial axons contained, simultaneously, NO synthase, vasoactive intestinal peptide and the acetylcholine-synthesizing enzyme choline acetyltransferase. Additionally, neuropeptide Y (NPY) was observed in a small percentage (12%) of neurons that increased to 39% after 36 h of organotypic culture. The CO synthesizing enzyme heme oxygenase-2 was detected only in perikarya but not in periarterial axons. Intrinsic vasodilator fibres were invariably present at arteries down to a luminal diameter of 150 μm, and reached 65% of section profiles of smallest arterioles, while noradrenergic and substance P-positive axons reached 80% of arteriolar profiles. These findings show that the intrinsic lingual vasodilator innervation of the guinea pig is far extending although slightly less developed than that by sensory and sympathetic axons, and differs both in this aspect and in patterns of colocalization from that reported for other organs, e.g. lung and pelvic organs.

Effect of interferon on human thymus microenvironment

Interferon, a thymic immunostimulator, was used with the aim of assessing the importance of adrenergic nerve fibers (ANF) and/or AChE-positive nerve fibers (AChENF) in the regulation of some immunological functions in humans. Thymic normal control fragments and/or thymic fragments of immunostimulated patients were removed during surgical biopsies. Thymic slices were stained with eosin-orange (for the recognition of microanatomical details of the microenvironment) and with Bodian's method for staining of nerve fibers. Histofluorescence microscopy was employed for staining ANF. AChENFs were detected by means of the direct-coloring thiocholine method. All images were submitted to quantitative morphometrical analysis and statistical comparisons of data. Moreover, the amount of proteins and noradrenaline was measured on thymic homogenates of the same patients. Treatment with interferon induces substantial changes in the thymic microenvironment, on ANF, on AChENFs and on the total amount of proteins and noradrenaline in thymic tissue homogenates. In conclusion immunostimulation with interferon induces substantial changes in the whole thymus and in its microenvironment, involving both sympathetic and parasympathetic nerve fibers.

125I-labeled galanin binding sites in congenital innervation defects of the distal colon.

Neuropeptides have turned out to be promising new parameters, in addition to the routinely performed histochemical diagnosis, of Hirschsprung's disease (HD). Studies of the peptidergic innervation of the affected intestinal segment of patients with HD have demonstrated a marked reduction in the density of several neuropeptide-containing nerve fibers. The frequency of nerve fibers storing the neuropeptide galanin (GAL) was found to be unchanged or slightly reduced in HD, but nothing is known about the occurrence of GAL receptors. In this study, in vitro receptor autoradiography using (125)I-labeled GAL and GAL immunofluorescence have been performed on frozen tissue sections from colon biopsies of 10 patients diagnosed with HD, 8 patients with intestinal neuronal dysplasia (IND B) and 20 patients with chronic obstruction but normal innervation. Binding sites were mainly detected in the mucosal and muscular layer, in acetylcholinesterase-positive nerve fiber bundles and ganglia within the submucosal layer and in close association to blood vessels. An increased population of GAL receptor positive, parasympathetic nerve fibers was seen in the aganglionic segment of HD as compared to controls and IND B. In contrast, GAL immunostaining which was unchanged in HD revealed a significant lack of GAL-positive structures in IND B colon biopsies. Colocalization of GAL and GAL binding sites was only observed in thick nerve fibers in the submucosa. The presence of GAL binding sites in different cellular structures suggests an involvement of GAL in various physiological functions of the gastrointestinal tract.

Autonomic control of the location and rate of the cardiac pacemaker in the sinoatrial fat pad of parasympathetically denervated dog hearts.

Parasympathetic activity predominates over sympathetic activity not only with respect to heart rate but also with respect to the pacemaker location in the dog heart. After we removed the parasympathetic neural elements in the sinoatrial (SA) fat pad in the right atrium, we observed that cervical vagus stimulation did not decrease the atrial rate, but it did suppress the increase in rate evoked by sympathetic stimulation. We determined whether the pacemaker rate and location were affected by presynaptic or postsynaptic mechanisms. We determined the earliest activation site by means of isochronic activation mapping of the right atrium of open chest, anesthetized dog hearts. An electrode array, which consisted of 48 unipolar electrodes, was used to record atrial activation. This array covered the three main pacemaker regions, including the SA node region. After parasympathetic nerve fibers in the SA fat pad had been denervated, vagus stimulation at 10 and 30 Hz did not decrease the heart rate, but it attenuated the increase in heart rate evoked by sympathetic stimulation or isoproterenol. Vagus stimulation at 10 Hz during sympathetic stimulation did not shift the earliest activation site from the superior pacemaker region to the SA node region in 11 of 18 experiments. However, vagus stimulation at 10 Hz during isoproterenol infusion shifted the earliest activation site to the SA node region in 11 of 13 experiments. More intense vagus stimulation during combined sympathetic stimulation or isoproterenol infusion shifted the earliest activation site to the SA node or the inferior pacemaker region in 15 of 18 and in all experiments, respectively. The results suggest that activation of parasympathetic elements not located in the SA fat pad attenuates the increase in heart rate and the shift in pacemaker location evoked by sympathetic activation. The sympathetic and parasympathetic effects interact at presynaptic and postsynaptic sites in the dog heart.

Identification and characterization of atrioventricular parasympathetic innervation in humans.

We hypothesized that in humans there is an epicardial fat pad from which parasympathetic ganglia supply the AV node. We also hypothesized that the parasympathetic nerves innervating the AV node also innervate the right atrium, and the greatest density of innervation is near the AV nodal fat pad. An epicardial fat pad near the junction of the left atrium and right inferior pulmonary vein was identified during cardiac surgery in seven patients. A ring electrode was used to stimulate this fat pad intraoperatively during sinus rhythm to produce transient complete heart block. Subsequently, temporary epicardial wire electrodes were sutured in pairs on this epicardial fat pad, the high right atrium, and the right ventricle by direct visualization during coronary artery bypass surgery in seven patients. Experiments were performed in the electrophysiology laboratory 1 to 5 days after surgery. Programmed atrial stimulation was performed via an endocardial electrode catheter advanced to the right atrium. The catheter tip electrode was moved in 1-cm concentric zones around the epicardial wires by fluoroscopic guidance. Atrial refractoriness at each catheter site was determined in the presence and absence of parasympathetic nerve stimulation (via the epicardial wires). In all seven patients, an AV nodal fat pad was identified. Fat pad stimulation during and after surgery caused complete heart block but no change in sinus rate. Fat pad stimulation decreased the right atrial effective refractory period at 1 cm (280 +/- 42 msec to 242 +/- 39 msec) and 2 cm (235 +/- 21 msec to 201 +/- 11 msec) from the fat pad (P = 0.04, compared with baseline). No significant change in atrial refractoriness occurred at distances >2 cm. The response to stimulation decreased as the distance from the fat pad increased. For the first time in humans, an epicardial fat pad was identified from which parasympathetic nerve fibers selectively innervate the AV node but not the sinoatrial node. Nerves in this fat pad also innervate the surrounding right atrium.

The anatomy and innervation of the mammalian pineal gland.

The parenchymal cells of the mammalian pineal gland are the hormone-producing pinealocytes and the interstitial cells. In addition, perivascular phagocytes are present. The phagocytes share antigenic properties with microglial and antigen-presenting cells. In certain species, the pineal gland also contains neurons and/or neuron-like peptidergic cells. The peptidergic cells might influence the pinealocyte by a paracrine secretion of the peptide. Nerve fibers innervating the mammalian pineal gland originate from perikarya located in the sympathetic superior cervical ganglion and the parasympathetic sphenopalatine and otic ganglia. The sympathetic nerve fibers contain norepinephrine and neuropeptide Y as neurotransmitters. The parasympathetic nerve fibers contain vasoactive intestinal peptide and peptide histidine isoleucine. Recently, neurons in the trigeminal ganglion, containing substance P, calcitonin gene-related peptide, and pituitary adenylate cyclase-activating peptide, have been shown to project to the mammalian pineal gland. Finally, nerve fibers originating from perikarya located in the brain containing, for example, GABA, orexin, serotonin, histamine, oxytocin, and vasopressin innervate the pineal gland directly via the pineal stalk. Biochemical studies have demonstrated numerous receptors on the pinealocyte cell membrane, which are able to bind the neurotransmitters located in the pinealopetal nerve fibers. These findings indicate that the mammalian pinealocyte can be influenced by a plethora of neurotransmitters.