I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors.

/pdf/glutamate-receptor-ion-channels-structure-regulation-and-148yts0p6h.pdf

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.

The Pharmacological Basis of Therapeutics

http://www.back-in-business-physiotherapy.com/images/files/DescendingControl.pdf

Descending control of pain.

Degeneration and regeneration of the nervous system

The current understanding of interactions of neurotransmitters with their receptors, leading to channel activation, inactivation, and desensitization, owes much to the discovery of highly specific drugs and toxins (Albuquerque and Daly, 1976; Albuquerque et al., 1979a; Karlin, 1980; Spivak and Albuquerque, 1982; Warnick et al., 1983). In addition, the use of electrophysiological techniques such as voltage clamp, and more recently patch clamp, has enabled investigators to examine the ionic currents underlying synaptic and electrical excitability with regard to population events [e.g., endplate currents (EPC) and ACh noise] and unitary events (single channel currents) while biochemical techniques, such as binding of radiolabeled ligands, affinity chromatography, and tracer flux assays, have allowed isolation, purification, and identification of the receptor channel macromolecule and its component parts. More recently, cloning studies have been useful in identification of the various subunits of the AChR and presumptive binding sites for the neurotransmitter (Noda et al., 1983a; Barnard and Dolly, 1982; Barnard et al., 1982). Such studies are of remarkable value in understanding function in nerve and skeletal muscle membranes. Beyond this, the role of synaptic and neuronal dysfunction in various neuropathic and musculoskeletal diseases is better understood.

Macromolecular Sites for Specific Neurotoxins and Drugs on Chemosensitive Synapses and Electrical Excitation in Biological Membranes

Behavioural effects of anatoxin, a potent nicotinic agonist, in rats.

The effects of the depolarizing agent, batrachotoxin (BTX), and of various analogs were studied on rat phrenic nerve-diaphragm muscle preparations at 37 degrees C. The structural modifications of BTX included: 1) replacement of the 20alpha-pyrrole-3-carboxylate moiety; 2) alterations of substituents on the pyrrole moiety; 3) clevage of the 3alpha, 9alpha-hemiketal linkage; and 4) quaternization of the tertiary nitrogen of BTX. All of the compounds except batrachotoxinin A (BTX-A), which lacks the 20alpha-substituent, depolarized the postsynaptic membrane, transiently increased the frequency of spontaneous transmitter release to 400 to 600 sec- minus 1 and finally produced blockade of the directly and indirectly elicited muscle twitches. Of the compounds tested, only BTX-A potentiated the muscle twitches. The concentration which elicits a 50% depolarization of the muscle membrane in 1 hour was determined for all the compounds except for BTX-A and for dihydrobatrachotoxin which lacks the 3alpha, 9alpha-hemiketal linkage; these two analogs never depolarized the postsynaptic membrane by more than 10 to 15%. BTX, the 20alpha-2, 4, 5-trimethylpyrrole-3-carboxylate of BTX-A and the 20alpha-ester of BTX-A with 2-ethyl-4-methylpyrrole-3-carboxylic acid (homobatrachotoxin) were the three most potent toxins with doses of 4.5, 12 and 18 times 10- minus 9 M eliciting a 50% membrane depolarization in 1 hour. The quaternary derivative of BTX, the 20alpha-4, 5-dimethylpyrrole-3-carboxylate of BTX-A and 20alpha-2,4-dimethyl-5-acetylpyrrole-3-carboxylate of BTX-A were 24-, 65- and 110-fold less potent than BTX as depolarizing agents, whereas the 20alpha-p-bromobenzoate of BTX-A was 220-fold less potent. Each of these derivatives had the ability to increase sodium permeability since the increase in spontaneous miniature end-plate potential frequency and membrane depolarization were reversed by tetrodotoxin or by reducing the external sodium concentration. BTX was found to be more effective at alkaline pH (pH 9.0), at which it exists almost entirely in the un-ionized form, than at physiological or acidic pH(6.0). The results indicate that the analogs of BTX act by a mechanism similar to that of the parent compound, but that their potency differs and certain compounds may have a more selective action on either the pre- or postsynaptic membrane. For maximal depolarizing activity, a substituted pyrrole moiety is necessary at the 20alpha-position of BTX-A and 3alpha, 9alpha-hemiketal linkage must remain intact providing rigidity for the pentacyclic steroid nucleus.

The pharmacology of batrachotoxin. VII. Structure-activity relationships and the effects of pH.

The natural alkaloid (-)PHY is a reversible anticholinesterase carbamate, but in contrast, its optical isomer (+)PHY, is a very weak anticholinesterase. We have shown that treatment of rats with atropine and (-)PHY prior to injections of a lethal dose of the irreversible organophosphate sarin (0.13 mg/kg) not only protected 100% of the animals from lethality but also reduced the size of the subneural lesions of the nicotinic synapses of skeletal muscle. Similar protection against lethality is provided by pretreatment with (+)PHY. At the concentration used (0.3 mg/kg), there was no detectable inhibition of AChE activity. We have examined the protection afforded by (+)PHY or (-)PHY against lethality and myopathy due to organophosphate agents such as sarin. The major alterations in the soleus motor endplates 1 hr after drug treatment were as follows: (1) A single sublethal dose of sarin (0.08 mg/kg) produced enlarged, blistered, and severely disrupted subjunctional regions, with muscle damage extendig beyond the endplate to include myofiber necrosis and subsequent phagocytosis; (2) (+)PHY (0.3 mg/kg) produced no obvious damage in the postjunctional region; (3) (-)PHY (0.1 mg/kg) had a selective effect in inducing irregularities of the subjunctional sarcomere band patterns without any gross vacuolization; (4) light microscopic data indicated that the combination of atropine and (+)PHY, or of atropine and (-)PHY (0.1 mg/kg), 30 min prior to a lethal dose of sarin, offered dramatic reduction in the average dimension of lesions. Lesions were detectable in most endplates but recognizable changes were markedly less severe than those seen in sarin myopathy. Few instances of extensive muscle damage and myofiber necrosis were visible.



In each of the 3 experimental groups examined, the extrajunctional myopathy was reversible with substantial recovery being observed on days 5 and 10 after drug treatment.



In addition to its anticholinesterase activity, (-)PHY is also a powerful ion channel blocker of the nicotinic acetylcholine receptor. As for (+)PHY, its protective effect almost certainly does not depend at inhibition of acetylcholinesterase, but as with (-)PHY, it my depend on a direct blockade at the nicotinic-acetylcholine receptor and its ion channel.

Enantiomer (+)physostigmine prevents organophosphate-induced subjunctional damage at the neuromuscular synapse by a mechanism not related to cholinesterase carbamylation.

Edson X. Albuquerque

Papers

Macromolecular Sites for Specific Neurotoxins and Drugs on Chemosensitive Synapses and Electrical Excitation in Biological Membranes

Behavioural effects of anatoxin, a potent nicotinic agonist, in rats.

The pharmacology of batrachotoxin. VII. Structure-activity relationships and the effects of pH.

Enantiomer (+)physostigmine prevents organophosphate-induced subjunctional damage at the neuromuscular synapse by a mechanism not related to cholinesterase carbamylation.

alpha-Cobratoxin blocks the nicotinic acetylcholine receptor in rat hippocampal neurons.