Nerve function nicotinic

Skeletal muscle relaxation and paralysis can occur from interruption of function at several sites along the pathway from the central nervous system (CNS) to myelinated somatic nerves, unmyelinated motor nerve terminals, nicotinic acetylcholine receptors, the motor end plate, the muscle membrane, and the intracellular muscular contractile apparatus itself. 

To achieve their different effects NTs are not only released from different neurons to act on different receptors but their biochemistry is different. While the mechanism of their release may be similar (Chapter 4) their turnover varies. Most NTs are synthesised from precursors in the axon terminals, stored in vesicles and released by arriving action potentials. Some are subsequently broken down extracellularly, e.g. acetylcholine by cholinesterase, but many, like the amino acids, are taken back into the nerve where they are incorporated into biochemical pathways that may modify their structure initially but ultimately ensure a maintained NT level. Such processes are ideally suited to the fast transmission effected by the amino acids and acetylcholine in some cases (nicotinic), and complements the anatomical features of their neurons and the recepter mechanisms they activate. Further, to ensure the maintenance of function in vital pathways, glutamate and GABA are stored in very high concentrations (10 pmol/mg) just as ACh is at the neuromuscular junction. 

Lindstrom, J.M. Nicotinic acetylcholine receptors of muscles and nerves comparison of their structures, functional roles, and vulnerability to pathology. Ann. N.Y. Acad. Sci. 998 41, 2003. 

ACh was first proposed as a mediator of cellular function by Hunt in 1907, and in 1914 Dale [2] pointed out that its action closely mimicked the response of parasympathetic nerve stimulation (see Ch. 10). Loewi, in 1921, provided clear evidence for ACh release by nerve stimulation. Separate receptors that explained the variety of actions of ACh became apparent in Dale s early experiments [2]. The nicotinic ACh receptor was the first transmitter receptor to be purified and to have its primary structure determined [3, 4]. The primary structures of most subtypes of both nicotinic and muscarinic receptors, the cholinesterases (ChE), choline acetyltransferase (ChAT), the choline and ACh transporters have been ascertained. Three-dimensional structures for several of these proteins or surrogates within the same protein family are also known. 

Paton WDM, Zaimis EJ (1949) The pharmacological actions of polymethylene bistrimethylammo-nium salts. Br J Pharmacol Chemother 4 381 00 Patrick J, Stallcup WB (1977) a-Bungarotoxin binding and cholinergic receptor function on a rat sympathetic nerve line. J Biol Chem 252 8629-8633 Patrick J, Boulter J, Deneris E, Wada K, Wada E, Connolly J, Swanson L, Heinemann S (1989) Structure and function of neuronal nicotinic acetylcholine receptors deduced from cDNA clones. Prog Brain Res 79 27-33... 

The principle of negative feedback control is also found at the presynaptic level of autonomic function. Important presynaptic feedback inhibitory control mechanisms have been shown to exist at most nerve endings. A well-documented mechanism involves an 2 receptor located on noradrenergic nerve terminals. This receptor is activated by norepinephrine and similar molecules activation diminishes further release of norepinephrine from these nerve endings (Table 6-4). Conversely, a presynaptic Breceptor appears to facilitate the release of norepinephrine. Presynaptic receptors that respond to the transmitter substances released by the nerve ending are called autoreceptors. Autoreceptors are usually inhibitory, but many cholinergic fibers, especially somatic motor fibers, have excitatory nicotinic autoreceptors. 

A second mechanism by which adenosine receptors may indirectly influence release is by regulating the rate of desensitization of other receptors. For example, at rat phrenic motor nerve terminals, Ai and A2A receptors inhibit and facilitate, respectively, acetylcholine release (Correia-de-Sd et al. 1991 Oliveira and Correia-de-Sd 2005). Additionally, they modulate nicotinic function, with A2A receptors accelerating and Ai receptors slowing the rate of desensitization of the aut-ofacilitatory nicotinic receptors (Correia-de-Sd and Ribeiro 1994b Timoteo et al. 2003 Duarte-Araujo et al. 2004), which influences the global effects of adenosine on transmitter release. 

Risso F, Grilli M, Parodi M et al (2004) Nicotine exerts a permissive role on NMDA receptor function in hippocampal noradrenergic terminals. Neuropharmacology 47 65-71 Rodrigues RJ, Alfaro TM, Rebola N et al (2005) Co-localization and functional interaction between adenosine A2A and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum. J Neurochem 92 433 41... 

GOthert M, Duhrsen U (1979) Effects of 5-hydroxytryptamine and related compounds on the sympathetic nerves of the rabbit heart. Naunyn Schmiedebergs Arch Pharmacol 308 9-18 Gotti C, Zoli M, Clementi F (2006) Brain nicotinic acetylcholine receptors native subtypes and their relevance. Trends Pharmacol Sci 27 482-91 Grady SR, Meinerz NM, Cao J, Reynolds AM, Picciotto MR, Changeux JP, McIntosh JM, Marks MJ, Collins AC (2001) Nicotinic agonists stimulate acetylcholine release from mouse interpeduncular nucleus a function mediated by a different nAChR than dopamine release from striatum. J Neurochem 76 258-68... 

The permeability of the skin to a toxic substance is a function of both the substance and the skin. The permeability of the skin varies with both the location and the species that penetrates it. In order to penetrate the skin significantly, a substance must be a liquid or gas or significantly soluble in water or organic solvents. In general, nonpolar, lipid-soluble substances traverse skin more readily than do ionic species. Substances that penetrate skin easily include lipid-soluble endogenous substances (hormones, vitamins D and K) and a number of xenobiotic compounds. Common examples of these are phenol, nicotine, and strychnine. Some military poisons, such as the nerve gas sarin (see Section 18.8), permeate the skin very readily, which greatly adds to then-hazards. In addition to the rate of transport through the skin, an additional factor that influences toxicity via the percutaneous route is the blood flow at the site of exposure. 

---