Chapter 3 - Cotransmission in the autonomic nervous system

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Abstract

After some early hints, cotransmission was proposed in 1976 and then “chemical coding” later established for sympathetic nerves (noradrenaline/norepinephrine, adenosine 5′-triphosphate (ATP), and neuropeptide Y), parasympathetic nerves (acetylcholine, ATP, and vasoactive intestinal polypeptide (VIP)), enteric nonadrenergic, noncholinergic inhibitory nerves (ATP, nitric oxide, and VIP), and sensory-motor nerves (calcitonin gene-related peptide, substance P, and ATP). ATP is a primitive signaling molecule that has been retained as a cotransmitter in most, if not all, nerve types in both the peripheral and central nervous systems. Neuropeptides coreleased with small molecule neurotransmitters in autonomic nerves do not usually act as cotransmitters but rather as prejunctional neuromodulators or trophic factors. Autonomic cotransmission offers subtle, local variation in physiological control mechanisms, rather than the dominance of inflexible central control mechanisms envisaged earlier. The variety of information imparted by a single neuron then greatly increases the sophistication and complexity of local control mechanisms. Cotransmitter composition shows considerable plasticity in development and aging, in pathophysiological conditions and following trauma or surgery. For example, ATP appears to become a more prominent cotransmitter in inflammatory and stress conditions.

Section snippets

Early studies

For many years, understanding of neurotransmission incorporated the concept that one neuron releases only a single transmitter, termed “Dale’s Principle” by Eccles (1957). This idea arose from a widely adopted misinterpretation of Dale’s suggestion in 1935 that the same neurotransmitter was stored in and released from all terminals of a single sensory neuron, a suggestion which did not specifically preclude the possibility that more than one transmitter may be associated with the same neuron (

Sympathetic nerves

There is compelling evidence that under certain conditions in vitro, single sympathetic neurons may release NA, ACh, or a mixture of these two transmitter substances (Le Douarin et al., 1975, Furshpan et al., 1976, Patterson et al., 1976). It seems likely that this represents a true reflection of events that occur in vivo during perinatal development (Hill and Hendry, 1977). It appears that a population of sympathetic nerve cells are present at birth that have the potential to synthesize both

Parasympathetic nerves

Evidence was presented for seasonal changes in release of ACh, 5-HT, histamine, and a peptide from vagus nerves supplying the frog stomach (Singh, 1964). The evidence for cotransmission of ACh and vasoactive intestinal polypeptide (VIP) in certain postganglionic parasympathetic neurons comes from pharmacological studies performed by Lundberg (1981) on cat salivary glands (see Fig. 3.2B). ACh and VIP are released from the same parasympathetic nerve terminals in response to transmural nerve

Sensory-motor nerves

The neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) are the principal transmitters of primary afferent nerves and have been shown to coexist in the same terminals (Gibbins et al., 1985, Rubino and Burnstock, 1996). Furthermore, with the use of colloidal gold particles of different sizes, they have been shown to coexist in the same large granular vesicles (Gulbenkian et al., 1986). The motor (efferent) function of sensory nerves has been demonstrated in rat mesenteric

Intrinsic enteric and cardiac neurons

Intrinsic neurons exist in most of the major organs of the body. Many of these are part of the parasympathetic nervous system, but certainly in the gut, and perhaps also in the heart and airways, some of these intrinsic neurons are derived from neural crest tissue, which differs from that which forms the sympathetic and parasympathetic systems, and appear to participate in local reflex actions independent of the CNS.

The enteric nervous system contains several hundred million neurons located in

Physiological significance of cotransmission

In general, autonomic cotransmission offers more diverse physiological control by mechanisms other than the all-or-none control by messages coming from the CNS that was the dominant view for many years (see Burnstock, 2004, Burnstock, 2009a) (Fig. 3.3).

Cotransmitter plasticity

Neurons possess the genetic potential to produce many neurotransmitters. The particular combination and quantity that results is partly preprogrammed and partly determined by “trophic” factors that trigger the expression or suppression of the appropriate genetic machinery. A number of studies have demonstrated plasticity of expression of autonomic nerves during development and aging, following trauma or surgery, after chronic exposure to drugs and in disease (Burnstock 1990c, Burnstock, 2006,

Concluding comments

A compelling body of evidence is now available to support the cotransmitter hypothesis, which implies more sophisticated local control mechanisms than were envisaged in earlier times. However, a number of issues still need to be resolved, including:

  • 1.

    resolution of the different roles of coexisting substances (including neurotransmitter, pre- and postjunctional neuromodulator and/or trophic roles) under different physiological conditions and patterns of discharge in the nerves

  • 2.

    identification of

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