John T. Stitt

A study of the mechanism of action of the mild analgesic dipyrone

The mechanism of action for the mild analgesics is controversial. While some have proposed that they inhibit prostaglandin synthesis in the central nervous system to interfere with nociceptive mediators in the brain, others have proposed that they act directly on nociceptive neural pathways to produce analgesia. This class of drugs also possesses antipyretic activity. We examined the antipyretic effect of one such drug, dipyrone, because this might elucidate the mechanism of its analgesic activity. In rats implanted with a femoral vein catheter and a cannula guide tube aimed towards the organum vasculosum laminae terminalis (OVLT) in the brain, an i.v. injection of 2 μg/kg interleukin-1β (IL-1β) produced a fever of 0.38±0.07°C while an injection of 20 ng prostaglandin E1 (PGE) into the OVLT produced a fever of 1.18±0.18°C. Dipyrone (25 mg/kg, i.v.) decreased the IL-1β fever but had no effect on the PGE fever. After pretreatment with the immunoadjuvant, zymosan, the IL-1β fevers were enhanced to equal those induced by PGE. Only 0.1 μg/kg, i.v. IL-1β raised body temperature by 1.20±0.10°C. An increased dose of dipyrone (50 mg/kg, i.v.) was required to attenuate this IL-1β fever; however, the PGE fever remained unaffected by this treatment with dipyrone. Thus, dipyrone treatment blocks IL-1β fever where synthesis of prostaglandin is a crucial step in the febrile process, but it has no effect on PGE fever where synthesis is bypassed. This suggests that dipyrone, probably through its active metabolites, inhibits prostaglandin synthesis to induce antipyresis and, by analogy, analgesia as well.

An analysis of the purinergic component of active muscle vasodilatation obtained by electrical stimulation of the hypothalamus in rabbits

1 In anaesthetized rabbits, electrical stimulation of the hypothalamus in areas analogous to the defence area in cats produces the ‘defence reaction.’ This response includes signs of arousal and a large increase in blood flow to skeletal muscle in the hind limb caused by a vasodilatation in the skeletal muscle vasculature. 2 The vasodilatation is a sympathetic response, and it is not dependent upon muscle activity in the hind limb. 3 The muscle vasodilatation is insensitive to α‐adrenoceptor, β‐adrenoceptor, cholinoceptor and histamine receptor antagonists. 4 Intra‐arterial injections of the purinoceptor agonists, adenosine triphosphate (ATP) and adenosine, mimic the vasodilatation produced by electrical stimulation. 5 The P1‐purinoceptor blocker, aminophylline, attenuates adenosine‐induced vasodilatation, but it does not affect the vasodilatation produced by ATP or hypothalamic stimulation. 6 The P2‐purinoceptor blocker, antazoline, attenuates the vasodilatation produced by both ATP and hypothalamic stimulation. 7 Our results suggest that the muscle vasodilatation produced by hypothalamic stimulation is mediated by purinergic nerves which release ATP and act on P2‐purinoceptors.

Body temperature regulation during euthermia and hyperthermia

Abstract : In this paper we have presented a few fundamental principles which are essential for an understanding of how microwaves might affect body temperature regulation. Application of the heat balance equation requires an accounting of all heat losses and heat gains. Thus, experimental measurements of these two processes are usually required to explain any thermoregulatory response. Knowledge of the individual elements of the thermoregulatory system and their integrative operation is imperative. Without such information one cannot hope to analyze or predict the consequences of microwave irradiation, or to separate simple heating effects from possible nonthermal effects. Finally, we have tried to emphasize that hyperthermia can be produced in different ways. Thus, there may be several forms of microwave hyperthermia, differing in their causality. Deposition of microwave energy in deep tissues might produce a response similar to exercise hyperthermia.

CNS CONTROL OF BODY TEMPERATURE

Publisher Summary This chapter discusses the central nervous system (CNS) control of body temperature. There is a multiplicative interaction between peripheral and central thermoreceptor inputs in the control of thermogenesis and perhaps other thermoregulatory effector outputs in mammals. Jacobson and Squires proposed a multiplicative relationship between ambient temperature and preoptic temperature in the regulation of oxygen consumption in cats. Bruck and Schwennicke demonstrated with the hyperbolic function that such a relationship existed between skin temperature, measured subcutaneously, and hypothalamic temperature in the control of nonshivering thermogenesis in the guinea pig. A similar type of control over heat production in the harbor seal has also been shown by Hammel et al. The chapter discusses a model that was proposed for the control of cold-induced thermogenesis in a rabbit. This model was predicated on a multiplicative interaction between mean skin temperature (Tsk) and preoptic anterior hypothalamic temperature (Thy). A distinctive feature of this model is that not only does it predict a decreasing hypothalamic thermosensitivity as the level of Tsk is increased but it also predicts that the Thy threshold for the onset of thermogenesis will decrease proportionately.

Hypothalamic generation of effector signals

Abstract The development of the widely-held hypothesis that the neurons that generate the single-unit activity observed in the hypothalamus are responsible for thermoregulatory effector signals is described. Serious objections to the continued acceptance of this hypotheses are discussed. Primarily these objections are: (1) the incompatibility of the described single-unit responses to pyrogens with whole-animal thermoregulatory responses to fever production; and (2) the recent demonstration that rostral brain stem single-unit activity in birds is similar to that described in mammals, yet birds lack an appropriate thermosensitivity within the preoptic anterior hypothalamic area. Alternative interpretations are discussed.

THE CAUSE OF RESTRAINT HYPOTHERMIA INDUCED IN COLD EXPOSED RATS

Publisher Summary This chapter discusses the cause of restraint hypothermia induced in cold exposed rats. The chapter describes a few experiments that were performed with the rats in a Plexiglas neck stock at an ambient temperature of 2°C. The first procedure was to restrain each naive rat in the cold. For restraint, a wide elastic band was placed about the rats waist. Restraint of naive rats caused rapid falls of T re , and the experiment was terminated when such falls reached 30°C. A few days later, the rats were reexposed to the cold but without restraint. The rats were then adapted at room temperature by restraining them for five days at least five hours each day. On the sixth day, the rats were again exposed to the cold while restrained. It was observed that in the naive state, the rat started with a T re near 37°C and an MR of about 10 watts/kg. When restraint was applied, MR fell to about 6 WT/kg, and T re fell steadily to reach 30°C 75 min later for a cooling rate of almost 6°C/h. Before restraint, EMG showed shivering activity, but after restraint, the EMG was silent, in accord with the reduced MR.