Experiments with guinea-pig lung suggest that some of the therapeutic effects of sodium salicylate and aspirin-like drugs are due to inhibition of the synthesis of prostaglandins.

Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs

The theory is advanced that the common denominator of a wide range of addictive substances is their ability to cause psychomotor activation. This view is related to the theory that all positive reinforcers activate a common biological mechanism associated with approach behaviors and that this mechanism has as one of its components dopaminergic fibers that project up the medial forebrain bundle from the midbrain to limbic and cortical regions. Evidence is reviewed that links both the reinforcing and locomotor-stimulating effects of both the psychomotor stimulants and the opiates to this brain mechanism. It is suggested that nicotine, caffeine, barbiturates, alcohol, benzodiazepines, cannabis, and phencyclidine----each ofwhich also has psychomotor stimulant actions--may activate the docaminergic fibers or their output circuitry. The role of physical dependence in addiction is suggested to vary from drug to drug and to be of secondary importance in the understanding of compulsive drug self-administration. Attempts at a general theory of addiction are attempts to isr late--from a variety of irrelevant actionsmthose drug actions that are responsible for habitual, compulsive, nonmedical drug self-administration. The common assumption of addiction theorists is that general principles of addiction can be learned from the study of one drug and that these principles will have heuristic value for the study of other drugs. Thus far, attempts at a general theory of addiction have failed to isolate common actions that can account for addiction across the range of major drug classes. A major stumbling block has been the psychomotor stimulants--amph etamine and cocainemwhich do not readily fit models traditionally based on depressant drug classes. The present article offers a new attempt at a general theory of addiction. It differs from earlier theories (e.g., Collier, 1968; Himmelsbach, 1943; Jaffe & Sharpless, 1968; Jellinek, 1960; Kalant, 1977; Lindsmith, 1947; Solomon & Corbit, 1974) in that it is based on the common denominator of the psychomotor stimulants---amphetamine, cocaine, and related drugs---rather than on the common denominator of the socalled depressant drugs~opiates, barbiturates, alcohol, and others. We take up two topics before presenting the new theory. First, we briefly discuss the heuristic value of a biological approach and suggest that the biologist's distinction between homology and analogy offers a useful insight. Next we discuss the shortcomings of earlier theories--variants of dependence theory. Then we outline the new theory and review the relevant evidence for its three major assertions: (a) that all addictive drugs have psychomotor stimulant actions, (b) that the stimulant actions of these different drugs have a shared biological mechanism, and (c) that the biological mechanism of these stimulant

A psychomotor stimulant theory of addiction

The study of pain in awake animals raises ethical, philosophical, and technical problems. We review the ethical standards for studying pain in animals and emphasize that there are scientific as well as moral reasons for keeping to them. Philosophically, there is the problem that pain cannot be monitored directly in animals but can only be estimated by examining their responses to nociceptive stimuli; however, such responses do not necessarily mean that there is a concomitant sensation. The types of nociceptive stimuli (electrical, thermal, mechanical, or chemical) that have been used in different pain models are reviewed with the conclusion that none is ideal, although chemical stimuli probably most closely mimic acute clinical pain. The monitored reactions are almost always motor responses ranging from spinal reflexes to complex behaviors. Most have the weakness that they may be associated with, or modulated by, other physiological functions. The main tests are critically reviewed in terms of their sensitivity, specificity, and predictiveness. Weaknesses are highlighted, including 1) that in most tests responses are monitored around a nociceptive threshold, whereas clinical pain is almost always more severe; 2) differences in the fashion whereby responses are evoked from healthy and inflamed tissues; and 3) problems in assessing threshold responses to stimuli, which continue to increase in intensity. It is concluded that although the neural basis of the most used tests is poorly understood, their use will be more profitable if pain is considered within, rather than apart from, the body's homeostatic mechanisms.

Animal Models of Nociception

This review is focused on purinergic neurotransmission, i.e., ATP released from nerves as a transmitter or cotransmitter to act as an extracellular signaling molecule on both pre- and postjunctional membranes at neuroeffector junctions and synapses, as well as acting as a trophic factor during development and regeneration. Emphasis is placed on the physiology and pathophysiology of ATP, but extracellular roles of its breakdown product, adenosine, are also considered because of their intimate interactions. The early history of the involvement of ATP in autonomic and skeletal neuromuscular transmission and in activities in the central nervous system and ganglia is reviewed. Brief background information is given about the identification of receptor subtypes for purines and pyrimidines and about ATP storage, release, and ectoenzymatic breakdown. Evidence that ATP is a cotransmitter in most, if not all, peripheral and central neurons is presented, as well as full accounts of neurotransmission and neuromodulation in autonomic and sensory ganglia and in the brain and spinal cord. There is coverage of neuron-glia interactions and of purinergic neuroeffector transmission to nonmuscular cells. To establish the primitive and widespread nature of purinergic neurotransmission, both the ontogeny and phylogeny of purinergic signaling are considered. Finally, the pathophysiology of purinergic neurotransmission in both peripheral and central nervous systems is reviewed, and speculations are made about future developments.

/pdf/physiology-and-pathophysiology-of-purinergic-1z94g2hz0f.pdf

Physiology and Pathophysiology of Purinergic Neurotransmission

Regulation of noradrenaline release by presynaptic receptor systems.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1968.tb00973.x

The abdominal constriction response and its suppression by analgesic drugs in the mouse

INTRAVENOUS administration of prostaglandin F2a (PGF2a) increases bronchial resistance in the cat1 and air overflow volume in the Konzett–Rossler preparation of guinea-pig lungs in vivo2. These effects suggest but do not prove that PGF2a contracts bronchial muscle. They might be caused by changes in fluid distribution in the lungs. Main3 and Horton and Main4 showed that prostaglandins E1, E2, E3, F1a and F2a relax cat isolated trachea. Because of the uncertainty about the action of PGF2a on tracheo-bronchial muscle and because this prostaglandin and PGE2 have been found in human lungs5,6, where they may affect the smooth muscle of the bronchial tree, we studied their effects on human isolated bronchial muscle. We also studied the effects of PGE1 and of mixtures of PGE1 or PGE2 with PGF2a on this smooth muscle preparation.

Effects of Prostaglandins on Human Bronchial Muscle

DRUG dependence can occur in organisms as far apart as bacteria1 and man, and even in isolated preparations of cells2 or muscle3. The theory proposed here is intended to explain the genesis in mammals of dependence on addictive drugs, such as morphine; but there seems no reason why it might not apply to drug dependence in other organisms or in isolated preparations and to tolerance towards non-addictive drugs. This explanation is based on the concept of Ehrlich4 that a chemical substance acts on a living system through its molecules becoming attached to particular sites (receptors) on cells. It uses the following aspects of receptor theory, which are to be found in pharmacological literature in other connexions.

A General Theory of the Genesis of Drug Dependence by Induction of Receptors

HISTAMINE, slow reacting substance in anaphylaxis (SRS-A) and prostaglandin F2α (PGF2α) are among substances obtained from lungs that contract human isolated bronchial muscle1–4. Fenamates antagonize bronchoconstriction induced by SRS-A but not that induced by histamine, and they lessen anaphylactic bronchoconstriction in the guinea-pig in vivo5–7. In view of the possibility, arising from these observations, that fenamates might be useful clinically against pathological bronchoconstriction, we explored how far meclofenamate (sodium N-(2,6-dichloro-m-tolyl) anthranilate)8 and flufenamate (sodium N-(α,α,α-trifluoro-m-toryl) anthranilate)9 antagonized the contraction of human isolated bronchial muscle induced by histamine, SRS-A or PGF2α.

Antagonism by Fenamates of Prostaglandin F 2α and of Slow Reacting Substance on Human Bronchial Muscle

The antagonism between analgesic antipyretic drugs and bradykinin was examined quantitatively, using the bronchoconstrictor response of guinea-pigs in vivo. The dose of bradykinin required to overcome antagonism by calcium acetylsalicylate increased with the dose of acetylsalicylate given, the ratio being roughly constant. Fifty times the quantity of acetylsalicylate which just antagonized bradykinin did not modify bronchoconstriction due to small doses of histamine, 5-hydroxytryptamine, or acetylcholine. A method of measuring the potency of this anti-bradykinin action was developed. Acetylsalicylic acid, phenylbutazone, amidopyrine, and phenazone had a high potency; paracetamol, cinchophen, sodium salicylate, and acetanilide had a moderate potency; and phenacetin, salicylamide, and 4-hydroxyisophthalic acid had little or none. Cortisone, hydrocortisone, aldosterone, amodiaquine, and morphine were ineffective or their action was non-specific. In sensitized guinea-pigs, an injection of antigen caused bronchospasm. This response was greatly lessened by pretreatment with mepyramine, but was not affected by calcium acetylsalicylate, lysergic acid diethylamide, or atropine. Acetylsalicylic acid, phenylbutazone, and amidopyrine did not specifically antagonize the action of bradykinin on the capillaries of guinea-pig skin in vivo, on guinea-pig ileum in vitro or on rat duodenum in vitro.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1960.tb00288.x

H. O. J. Collier

Papers

The abdominal constriction response and its suppression by analgesic drugs in the mouse

Effects of Prostaglandins on Human Bronchial Muscle

A General Theory of the Genesis of Drug Dependence by Induction of Receptors

Antagonism by Fenamates of Prostaglandin F 2α and of Slow Reacting Substance on Human Bronchial Muscle

Analgesic antipyretic drugs as antagonists of bradykinin.