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Summary1. The effects of cocaine, 6-hydroxydopamine (6-OHDA), reserpine and 17-,8-oestradiol on the sensitivity of the rat anococcygeus muscle to noradrenaline (NA), acetylcholine (ACh) and KCl were investigated.2. Cocaine (10-5M) increased the sensitivity of the anococcygeus to NA (100-fold) but not to ACh or KCl. 3. 6-OHDA treatment, whether discontinuous over 6 days or continuous for 12 days, also produced a specific increase in sensitivity to NA (50-fold).4. Reserpine ( (1 mg/kg)/day) produced a small increase in sensitivity of the muscle to NA and ACh but not to KCI, after 6 days and 12 days treatment.5. 17-,8-Oestradiol (10-5M) had no effect on the sensitivity of the anococcygeus to NA or ACh, but reduced the sensitivity to KCI and the possible mechanism of this effect is discussed.6. Cocaine increased, while reserpine, 6-OHDA and 17-f3-oestradiol decreased, the maximum response of the muscle to KCI. The response to KCI was shown to consist of at least three components; a direct action on the muscle, an effect due to release of NA, and an inhibitory action, probably due to release of the unknown inhibitory transmitter. hntroductionIn adrenergically-innervated tissues, supersensitivity of either surgical or pharma-

1 Morphine and leucine-and methionine-enkephalins inhibited the contractile response of the pithed rat colon to electrical stimulation of the spinal motor outflows and inhibited motor responses of the isolated colon to field stimulation. 2 Morphine and the opioid peptides also had an excitatory action in the colon. In the pithed rat, opiates caused regular fluctuations in intracolonic pressure and in the isolated colon, caused regular waves of contraction. This excitatory response was produced by low concentrations of the enkephalins (2 x 10'8 M, 2 x 10o-M), was stereospecific and was antagonized by naloxone.3 Opiate-induced contractions in the isolated colon were inhibited by catecholamines, adenine nucleotides and by phosphodiesterase inhibitors. These contractions were unaffected by ergotamine and tolazoline, or by propranolol. 4 The excitatory action of opiates in the isolated colon was not antagonized and usually was potentiated by atropine, (+ -tubocurarine and hexamethonium. In the absence of opiates, these drugs also produced similar waves of contraction, which were unaffected by naloxone. 5 Opiate-induced contractions occurred in colon rendered unresponsive to 5-hydroxytryptamine (5-HT) and these contractions were potentiated by the 5-HT antagonist, lysergic acid diethylamide, which, when administered alone, caused similar contractions. The 5-HT antagonist, cyproheptadine, inhibited opiate-induced contractions but was non-specific, since it also inhibited responses of the colon to carbachol and KCI. 6 Opiate-induced contractions were unaffected by procaine and were potentiated by tetrodotoxin. Both of these drugs, when administered alone, produced waves of contractions, which were similar to those produced by opiates but were unaffected by naloxone. 7 Contractions produced in the isolated colon either by opiates, atropine or (+ )tubocurarine, or any combination of these drugs, were inhibited by field stimulation applied at the peak of a wave of contraction. This inhibitory response to field stimulation occurred at low frequencies of stimulation (< 10 Hz), and persisted in colon from rats pretreated with reserpine to deplete, or 6-hydroxydopamine to destroy, adrenergic nerve endings. It was unaffected by guanethidine but abolished by tetrodotoxin. 8 The implications of these results are considered and it is concluded that the excitatory action of opiates in the rat colon is probably not mediated by the release of acetylcholine or 5-HT but instead, may be due either to a direct action on smooth muscle or to a presynaptic inhibitory action at a ganglionic site in a non-adrenergic inhibitory mechanism, which normally suppresses myogenic activity.