1A modified abdominal constriction test, whereby the drugs used are injected intraperitoneally when the writhing response is maximal, has been used to study the antinociceptive activity of various sympathomimetic drugs. Of those tested, clonidine was the most potent, with an ID50 value in the nanomolar range. (-)-Isoprenaline, (-)-adrenaline and (-)-noradrenaline were only a little less potent. Phenylephrine, the least potent, had only about one-sixtieth of the activity of clonidine. 2 The antinociceptive action appears to occur within the peritoneum, since it was apparent almost immediately after the drugs were injected and was produced by doses far smaller than were effective by the subcutaneous route. 3 ac-Adrenoceptors appear to be involved in the reaction, since noradrenaline showed stereospecificity, and the a-adrenoceptor antagonists phentolamine and piperoxan both shifted the dose-response curves of the a-adrenoceptor agonist drugs to the right, usually parallel to the control curves.4 The high antinociceptive potency of clonidine and oxymetazoline, indicate the importance of a2-adrenoceptors and this was supported by the finding that piperoxan was a more effective antagonist than phentolamine. The moderate potency of phenylephrine suggests that aoadrenoceptors may also be involved, although the selective al-antagonist, prazosin, did not antagonize noradrenaline and had antinociceptive activity of its own. 5 P-Adrenoceptors also appear to be involved in the antinociceptive response, since propranalol antagonized the effect of isoprenaline, but not that of clonidine. 6 Piperoxan was a very effective antagonist of morphine, while phentolamine had a weaker action. Naloxone had little action against the a-adrenoceptor agonists. 7 Mice pretreated with clonidine or oxymetazoline but not noradrenaline showed a very great cross-tolerance to morphine. Morphine pretreatment caused marked desensitization of itself, but little cross-tolerance to clonidine or oxymetazoline.8 It is suggested that sensory nerves in the mouse peritoneum have a2-and P-adrenoceptors on their terminals, and possibly al-receptors also. It is possible that when activated by the appropriate agonists they depress the generation of pain impulses. There is an interaction between the a-adrenoceptors and opioid receptors in the mouse peritoneum.

1 A modification of the abdominal constriction test in mice has been developed, and used to study the antinociceptive effects of morphine and several related drugs. In most experiments, acetic acid (0.6% i.p.) was used as the nociceptive stimulus, and in a few cases, acetylcholine (3.2 mg/kg i.p.) was used. When the abdominal constriction response had reached a maximum, the drugs under test were given intraperitoneally, and their ability to decrease the number of abdominal constrictions was determined, beginning immediately after its administration. The aim of this study was to investigate the possibility that morphine and its congeners may produce an antinociceptive effect,by an action within the peritoneum.2 It was found that morphine was an extremely potent antinociceptive agent in this modified test, with an ID50 of 5.4 x 10-9 mol/kg (1.54 pg/kg). Codeine and pentazocine were about 40 times less active and oxymorphine was about twice as potent as morphine. Met-and Leu-enkephalin were also potent but their action diminished very rapidly with time. Ketocyclazocine was the most potent substance tested, and had an ID50 value of 1.26 x 10-10 mol/kg (0.036 ,ug/kg). All the drugs tested produced their maximal effect within 1 or 2 min of administration.3 Pretreatment of the mice with naloxone caused a dose-dependent shift to the right of the dose-response curve to morphine. The pAx plot was linear over part of the range, with a slope of -1.02 and the 'apparent pA2' value was 6.14. Naloxone was much less effective in antagonizing Met-enkephalin, and caused a slight potentiation of ketocyclazocine and pentazocine and of cocaine, which was used for comparison. 4 Pretreatment of mice with morphine, 3 h earlier, caused a marked tolerance to a subsequent dose of morphine, and a potentiation of the antagonist potency of naloxone. However, there was little cross-tolerance between morphine and Leu-enkephalin. 5 It is concluded that morphine and its congeners can produce an antinociceptive effect by an action within the mouse peritoneum, presumably by interacting with one or more types of opioid receptors which may be situated on sensory nerve endings.

The contractions of the guinea-pig isolated vas deferens elicited by electrical stimulation of the hypogastric nerve were completely blocked by the following drugs: guanethidine, bretylium, dimethylphenylpiperazinium hydrochloride, nicotine, pempidine, hexamethonium, hemicholinium, D-tubocurarine and procaine. However, when the vas deferens was stimulated through an electrode in its lumen, the contractions in response to frequent, short stimuli (50 shocks/sec, I msec duration) were blocked by guanethidine, bretylium and dimethylphenylpiperazinium, but were not affected by the remaining drugs, except that procaine and hemicholinium each caused some reduction in the responses.When the preparation was stimulated transmurally with shocks of 200 msec duration at 1 shock/sec, the contractions were unaffected by any of the above drugs, except hemicholinium which again caused a slow reduction of up to 50% of the original response. It is concluded that nicotine, pempidine, hexamethonium, D-tubocurarine and hemicholinium probably block the response to stimulation of the hypogastric nerve by acting on peripheral ganglia in its pathway. Hemicholinium appears to have an additional effect in depressing the responses of the smooth muscle of the vas deferens to direct electrical stimulation, and procaine may act both on the ganglia and at the nerve terminals.

The effects of various drugs which block sympathetic nerves have been studied in Finkleman preparations of rabbit and cat ileum. Contractile responses could be produced in many cases after the normal inhibitory responses to periarterial nerve stimulation had been blocked. In almost all cases this contractile response was abolished by ganglion-blocking drugs. The normal rabbit ileum Finkleman preparation was found to behave differently towards bretylium than do preparations taken from animals treated with reserpine. The block of the guinea-pig isolated hypogastric vas deferens preparation caused by hemicholinium HC-3 was found to be reversed in the presence of noradrenaline, histamine, or 5-hydroxytryptamine, as was the block caused by guanethidine and bretylium. The results are discussed in relation to the Burn-Rand theory of sympathetic nerve mechanism.