MILTON AND SABINE WENDLANDT

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326 A. S. MILTON AND S. WENDLANDT INTRODUCTION The results of the present experiments show that the prostaglandin E1 (PGE1) and E2 (PGE2) exert a strong hyperthermic effect when injected in minute amounts into the third cerebral ventricle of the unanaesthetized cat and rabbit. Prostaglandins have been shown to be natural constituents of the central nervous system of various species including cats and rabbits (Samuelsson, 1964; Coceani & Wolfe, 1965; Ambache, Brummer, Rose & Whiting, 1966; Horton & Main, 1967a). The distribution of the E and F series of prostaglandins has been investigated in the central nervous system of the dog by Holmes & Horton (1968 a), who found them not only in the cerebral cortex, cerebrum and spinal cord, but also in those parts of the brain which line the cerebral ventricles such as the hippocampus, caudate nucleus and hypothalamus. They appear to be released from these structures into the perfused cerebral ventricular system as shown in anaesthetized cats (Feldberg & Myers, 1966) and dogs (Holmes, 1970). According to Holmes the concentration of the E series of prostaglandins increases fourfold on perfusion with 5-hydroxytryptamine. Prostaglandins were also detected in superfusate from the cerebral and cerebellar cortex (Ramwell & Shaw, 1966; Wolfe, Coceani & Pace-Asciak, 1967). No definite physiological function has so far been attributed to the prostaglandins in the central nervous system but they have been shown to modulate nerve cell activity (Avanzino, Bradley & Wolstencroft, 1966; Hoffer, Siggins & Bloom, 1969; Kaplan, Grega & Buckley, 1968; Duda, Horton & McPherson, 1968; Phillis & Tebecis, 1968) and to alter animal behaviour, to produce signs of sedation, stupor and catatonia in cats, to antagonize electrical and leptazol induced convulsions in rats and to affect muscle tone and reflex activity in various species (for references see Horton, 1968). The results of the present experiments suggest that PGE1 and PGE2 by their hyperthermic actions may play a role in temperature regulation and that this may be one of their physiological functions in the hypothalamus. METHODS Cats and Dutch rabbits of either sex weighing between 2-5 and 3-5 kg were used. Cannulation of third ventricle. The cats were anaesthetized with pentobarbitone sodium (40 mg/kg i.P.). The head of the cat was held in a stereotaxic apparatus, the eardrums being protected by rubber caps fitted onto the earbars. Under aseptic conditions, a hole 1-5 mm in diameter was drilled through the bone in the midline and 12-5 mm anterior to the interaural line. A stainless-steel guide cannula (20-gauge needle tubing) with a rubber-capped cannula head was lowered through the hole in the skull to 6 mm above the interaural line. This placed the guide cannula in the
PROSTAGLANDINS AND BODY TEMPERATURE 327 third ventricle at the level of the anterior hypothalamus. The co-ordinates were taken from the stereotaxic atlas of the cat brain by Snider & Niemer (1961). The rabbits were anaesthetized with paraldehyde (1-5 ml./kg i.P.) and a rubbercapped cannula similar to that used in the cat was implanted into the third ventricle 7-5 mm posterior to the coronal suture and to a depth of 13-5 mm from the surface of the skull. Correct implantation of the cannula in both cat and rabbit was apparent by the pulsatile flow of c.s.f. from a needle inserted into the rubber cap of the cannula. Once flow was established the cannula was fixed to the bone with acrylic cement anchored by two stainless-steel screws screwed into the skull. Benzyl-penicillin powder was sprinkled on to the wound and 2000 units were injected intramuscularly daily for 3 days. The cannula and cannula holder were heat sterilized and flushed with pyrogen-free saline before implantation. The animals were allowed to recover for at least a week before being used for experiments. Temperature measurement. The experiments were performed at an ambient temperature of 20-22° C unless otherwise stated. The cats moved about freely in the cage while the rabbits were restrained in a rabbit holder. Temperature was measured with a thermistor probe (Yellow Springs 400) inserted about 8 cm into the rectum and held in position with adhesive tape. Temperature was monitored continuously by a Honeywell multi-channel chart recorder. The temperature responses were plotted on graph paper with time (1 cm = 1 hr) as abscissa, and temperature change (2 cm = 10 C) as ordinate. The number of cm2 between the curve and the base line was counted and divided by two, to give a thermal response index (TRI). Each unit of TRI is equivalent therefore to a 1° C change lasting for 1 hr. Administration of drugs. Solutions were injected into the third ventricle via a polyethylene tube attached to a cannula made of 27-gauge stainless-steel needle tubing. Both tube and cannula were filled with the solution and the cannula was passed through the rubber diaphragm of the previously implanted guide cannula. A flange around the inner cannula prevented it from extending more than 1-0 mm beyond the tip of the outer guide cannula. A control injection of 5 ,I. pyrogen-free 0-9 % NaCl solution was given 1-2 hr before each prostaglandin injection. The prostaglandins were injected in a volume of 5 or 10 Al. Immediately after the injection the cannula was flushed with 5 Id. sterile 0 9 % NaCl solution. In several experiments in which the effect of Paracetamol (4-acetamidophenol; 4-Ac) on the hyperthermia produced by PGE1 and PGE2 was examined it was injected I.P. in a dose of 50 mg/kg. The 4-Ac was dissolved in 2-0 ml of hot 0-9 % NaCl solution containing 20 % propylene glycol and, before injection, made up with 0 9 % NaCl solution to 4 ml. A similar volume of propylene glycol saline containing no 4-Ac was used for control injections. Preparation of pyrogen-free prostaglandin solutions. Stock solutions of the prostaglandins in methanol were stored at - 150 C. A sterile solution suitable for intraventricular injection was prepared from the stock solution by the following procedure. The methanol was evaporated using a rotary evaporator with a water bath temperature of 400 C. The pure prostaglandin residue was dissolved in sterile pyrogen-free 0 9 % NaCl solution and passed through a GS 0-22 ,m 'Millipore' filter before injection. The 'Millipore' filter was sufficiently fine to remove any particulate matter including bacteria. The filtered solution was stored at - 150 C until required, and was thawed and warmed to room temperature before injection. All glassware and the 'Millipore' filter unit were autoclaved before use.
Page 1: J. Physiol. (1971), 218, pp. 325-33
Page 5 and 6: No. of expts. 3 3 2 3 PROSTAGLANDIN
Page 7 and 8: PROSTAGLANDINS AND BODY TEMPERATURE

MILTON AND SABINE WENDLANDT

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