Non-nicotinic transmission in autonomic ganglia revisited – an important physiological function?

Autonomic ganglia, in particular sympathetic ones, have fascinated investigators since ancient times. It was believed that these structures are ‘little brains’ that integrate, carry and distribute the ‘animal spirits’ from the brain to the periphery leading to coordinated actions of the peripheral target organs (the ‘sympathies’) in association with the activity of the brain (McLachlan, 1995). However, their primary function is to distribute messages to the periphery from relatively small pools of preganglionic neurones to large pools of postganglionic neurones. Integration occurs in some sympathetic pathways of prevertebral ganglia (Jänig, 1995). The primary transmitter in all ganglia is acetylcholine (ACh) acting on nicotinic receptors. ACh released by preganglionic fibres also acts on muscarinic receptors and preganglionic fibres may release neuropeptides, both generating slow excitatory synaptic potentials (EPSPs) in some types of postganglionic neurone by decrease of potassium conductance (M currents). What is the function of these slow EPSPs in postganglionic neurones? The paper by Morris et al. (2005) in this issue of The Journal of Physiology describes experiments on an in vitro preparation of the anterior pelvic (paracervical) ganglia with attached uterine artery and nerves that contain the preganglionic sympathetic or parasympathetic axons innervating the postganglionic vasodilator (VD) neurones to the uterine artery. Repetitive electrical stimulation of the preganglionic axons dilates the artery. This preganglionically induced VD is generated by release of NO and VIP, outlasts the train of stimuli by more then 10 min, and is only slightly reduced in amplitude and delayed after complete block of nicotinic transmission in the paracervical ganglia. It is generated by continuous discharge of the postganglionic VD neurones produced by a slow EPSP. The transmitter involved is unknown (but unlikely to be substance P, ATP, 5-HT, glutamate or ACh (muscarinic action)). The continuous discharge of the postganglionic neurones cannot be due to a long-term potentiation of cholinergic nicotinic transmission since VD neurones in the paracervical ganglia receive synaptic inputs from two preganglionic fibres, one being strong (i.e. always suprathreshold).

The results of Morris et al. (2005) compare with those obtained more than 20 years ago in vivo in the cat. Repetitive electrical stimulation of preganglionic axons in the lumbar sympathetic trunk (LST; 50 stimuli at 25 Hz) elicits, in a decentralized preparation, early high frequency discharges and late cholinergic mucarinic and/or non-cholinergic long-lasting afterdischarges in many postganglionic neurones supplying the cat hindlimb (Fig. 1B). These afterdischarges can only be elicited when small-diameter (largely unmyelinated) preganglionic axons are stimulated (Jänig et al. 1984); they require trains of 50 stimuli of at least 3–4 Hz or 3–10 stimuli at 25 Hz, and only occur in vasoconstrictor (VC) neurones (most muscle (MVC) and some 30% cutaneous VC neurones) but not in sudomotor or pilomotor neurones (Hoffmeister et al. 1978). In a preparation with intact LST the rate of ongoing activity in VC neurones is enhanced for 4–40 min or longer following repetitive stimulation of the small-diameter preganglionic axons (Fig. 1C). This enhancement can also be elicited heterosynaptically and is associated with a long-lasting decrease of blood flow (Blumberg & Jänig, 1983; Jänig & Koltzenburg, 1991). Stimulation of arterial chemoreceptors by hypoxia (8% O₂ in N₂) excites MVC neurones. This reflex excitation is also present in many MVC neurones after blockade of nicotinic transmission or of both nicotinic and muscarinic transmission (Fig. 1D) (Jänig et al. 1983).

Figure 1. Muscarinic and non-cholinergic responses elicited in postganglionic vasoconstrictor neurones (skin (CVC), muscle (MVC)) projecting to the cat hindlimb by activation of preganglionic neurones.

A, experimental set-up. B, electrical stimulation of preganglionic axons in the lumbar sympathetic trunk (LST) suprathreshold for all fibres with 50 stimuli at 25 Hz in a decentralized preparation (preganglionic axons cut). Afterdischarges in 2 CVC neurones before and after atropine. C, preganglionic axons intact. Long-lasting enhancement of activity in a CVC neurone following suprathreshold electrical stimulation of all preganglionic fibres in the LST. Inset: Original activity. D, reflex activation of a postganglionic MVC neurone to stimulation of arterial chemoreceptors by ventilating the cat with a hypoxic gas mixture during complete block of cholinergic transmission (26 mg kg⁻¹ hexamethonium (C6) infused into the iliac artery in the presence of atropine (1 mg kg⁻¹). Inset: response of the MVC neurone to repetitive stimulation of the preganglionic axons in the LST (50 stimuli at 25 Hz) under complete block of cholinergic transmission. E, myelinated preganglionic fibres conducting at > 3 m s⁻¹ generate only nicotinic responses in VC neurones. Repetitive stimulation of unmyelinated and some small diameter myelinated preganglionic axons (conduction velocity < 3 m s⁻¹) may generate, in addition to nicotinic reponses, non-nicotinic (muscarinic or non-cholinergic (possibly peptidergic)) responses. Most muscarinic and non-cholinergic receptors probably are located extrajunctionally. B from Hoffmeister et al. (1978); C from Blumberg & Jänig (1983); D from Jänig et al. (1983).

In conclusion, non-nicotinic (muscarinic and/or peptidergic) synaptic transmission in postganglionic VC neurones may be important under certain functional conditions (Fig. 1E). Infrequent bursts of impulses in preganglionic neurones with slowly conducting axons that converge on postganglionic VC neurones are necessary to generate a long-term increase in ongoing activity in postganglionic VC neurones. This may also apply to the VD and secretomotor pathways supplying the internal reproductive organs in females, leading via a non-cholinergic mechanism in paracervical ganglia to long-lasting effector responses (vasodilatation, secretion) as shown by Morris et al. (2005). These results tie up with observations in the cat that preganglionic non-VC neurones projecting in lumbar splanchnic nerves can be activated reflexly for 1–12 min after mechanical stimulation of sacral afferents for 20 s (e.g. from the anal canal; Bahr et al. 1986). The mechanism underlying this unique reflex activation that outlasts the afferent stimulus by many minutes is most likely to lie within the spinal pathways. Thus, it may be hypothesized that a centrally potentiated reflex in preganglionic neurones, that probably have VD and secretomotor function, is further amplified by non-cholinergic synaptic transmission in paracervical ganglia. This sequential cascade of amplification of a central signal might turn out to be of considerable importance in the regulation of the reproductive organs.