John F. Howes

The effect of narcotics and narcotic antagonists on the tail‐flick response in spinal mice

Irwin, Houde & others (1951) reported that the tail-flick response of rats to radiant heat has the characters of a simple reflex. The ability of spinal rats to respond to this stimulus has been confirmed and extended (Winter & Flataker, 1951 ; Bonnycastle, Cook & Ipsen, 1953). Morphine inhibited the reflex in spinal rats but a quantitative difference observed between its effect in spinal rats and intact animals indicated that a second action might exist in its capacity to increase supraspinal inhibitory mechanisms. We have used the tail-flick test in mice to elucidate the mechanism of action of morphine and the narcotic-antagonist analgesics (Harris & Pierson, 1964 ; Dewey, Harris & others, 1969 ; Harris, Dewey & others, 1969) and have found a high correlation of activity with a number of narcotic analgesics to exist between species. We have confirmed and extended the observation that cholinergic agents such as oxotremorine and physostigmine also reduced this response (Harris & others, 1969; Howes, Harris & others, 1969). In addition, we have shown that an increase in central adrenergic or 5-hydroxytryptamine tone will increase the activity of morphine in intact mice in the tail-flick test (Dewey, Harris & others, 1968). We have now attempted to increase our knowledge about this testing procedure by studying the narcotics, the narcotic antagonists, and some of the neurochemicals discussed above in spinal mice. Male albino mice of the Swiss-Webster strain (18-25 g) had transections made under ether anaesthesia. A dorsal midline incision was made and the spinal cord was exposed between the fifth and sixth thoracic vertebrae. The cord was cauterized and the wound was closed with silk sutures. Attempts to transect the cord at a higher level resulted in death from respiratory paralysis or uncontrolled bleeding. There were few deaths from the surgical procedure. Water and food were presented ad libitum. Within 3 to 4 h all mice were quite active. Simple physiological stimuli showed that the cord section was positive. Most of the mice responded to the radiant stimulus of the tail-flick apparatus within 4 s, the variability among the reaction times being less than is usually observed in normal mice. Animals not responding within 4 s were not used. The results obtained were averaged with a second reading taken 30 min later, after which the drug was given subcutaneously in the flank; readings were made 20 min later. Mice not responding within 10 s were removed from the apparatus and considered to be 100% affected. The % maximal possible inhibition was calculated using the following formula :

Sustained release of sulphadiazine

An implantable system was developed which released sulphadiazine in mice over an extended period of time efficacious against infective challenges by Plasmodium berghei. The most successful preparation was a copolymer of L(+)‐lactic acid + (±)‐lactic acid (90 and 10% by weight, respectively) with a molecular weight of 150 000, with which sulphadiazine was mixed at 33.3% of the total weight, in a formulation as beads of 1.5 mm diameter. This preparation released sulphadiazine at a nearly constant rate over three months as measured by the appearance in urine of mice of radioactivity from [35S] sulphadiazine in transplanted material. When implanted in mice, the beads gave effective protection against repetitive (weekly) infective challenges with P. berghei by implanted beads at dosages equivalent to 57 mg kg−1 sulphadiazine and greater over 21 weeks.

Water-Soluble Derivatives of Δ1 Tetrahydrocannabinol

Δ1-Tetrahydrocannabinol, which is resinous and insoluble in water and therefore difficult to study pharmacologically, can be converted to a watersoluble derivative without loss of its biological activity. This has been achieved by preparing esters bearing a nitrogen moiety with the use of carbodiimide as the condensing agent. The availability of such water-soluble derivatives will allow the evaluation of Δ1-tetrahydrocannabinol in self-administration studies in monkeys for its addiction liability potential in man. This technique of water solubilization is also applicable to other compounds of chemical and biological significance.

Novel opiates and antagonists. 6. 7-Alkyl-6,7-didehydromorphinans

A method for preparing a variety of 7-alkyl-6,7- didehydromorphinans from the corresponding 6- morphinanones is described. The key intermediates in this sequence are the 7-formyl derivatives. The two epimeric B/C-trans-7-(1- hydroxypentyl ) morphinans ( 16a ,b) are stereochemically similar to the endo- ethanotetrahydrooripavines and are extremely potent in the mouse writhing test. The corresponding B/C-cis -7-(1- hydroxypentyl ) morphinans are inactive in this test.

Water-soluble derivatives of 1 -tetrahydrocannabinol.

Δ1-Tetrahydrocannabinol, which is resinous and insoluble in water and therefore difficult to study pharmacologically, can be converted to a watersoluble derivative without loss of its biological activity. This has been achieved by preparing esters bearing a nitrogen moiety with the use of carbodiimide as the condensing agent. The availability of such water-soluble derivatives will allow the evaluation of Δ1-tetrahydrocannabinol in self-administration studies in monkeys for its addiction liability potential in man. This technique of water solubilization is also applicable to other compounds of chemical and biological significance.

Water-Soluble Derivatives of Dgr1 Tetrahydrocannabinol

Δ1-Tetrahydrocannabinol, which is resinous and insoluble in water and therefore difficult to study pharmacologically, can be converted to a watersoluble derivative without loss of its biological activity. This has been achieved by preparing esters bearing a nitrogen moiety with the use of carbodiimide as the condensing agent. The availability of such water-soluble derivatives will allow the evaluation of Δ1-tetrahydrocannabinol in self-administration studies in monkeys for its addiction liability potential in man. This technique of water solubilization is also applicable to other compounds of chemical and biological significance.