The effects of N‐(cyclopropylmethyl)‐19‐isopentyl‐nororvinol (M320), a potent agonist at k‐ and μ‐ opiate receptors, on urine excretion of rats

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Abstract
1 The effects of N-(cyclopropylmethyl)-19-isopentylnororvinol hydrochloride (M320) on urine excretion by rats were investigated. Further studies, using rabbit isolated vas deferens, investigated its interactions with k-opiate receptors. 2 The output of urine for a 2 h period after M320, administered subcutaneously to normally hydrated Long Evans rats, showed a bell-shaped dose-response relationship, the maximum effect occurring after 10 μg kg−1. Urinary retention contributed to but did not fully account for the weaker diuresis after high doses. Attenuation of the ascending portion of the dose-response curve to M320 occurred after 1 and 10 mg kg−1 but not 0.1 mg kg−1 of naltrexone intraperitoneally. 3 M320 in low doses (3–10 μg kg−1) caused a small but significant increase in sodium excretion. M320 (30 μg kg−1) reduced both sodium and potassium excretion. 4 M320 (10 μg kg−1 s.c.) did not increase the volume of urine voided in 2 h by Brattleboro rats showing diabetes insipidus, even when urine excretion was reduced to normal by 1 week of vasopressin replacement. 5 The volume of urine voided in 4 h by Brattleboro rats was progressively reduced to zero by M320 (10–100 μg kg−1 s.c). Urinary retention contributed to but did not account for this reduction. 6 Plasma levels of immunoreactive arginine vasopressin (ir-AVP) were reduced in both normal and dehydrated Long Evans rats after doses greater than 1 μg kg−1 M320 s.c. 7 In vitro, M320 caused persistent inhibition of twitches of the electrically stimulated rabbit vas deferens (IC50 1.7 nM). 8 These data suggest that M320 has potent opioid agonist activity at k-receptors and at higher concentrations stimulates μ- receptors. In the rat, its activity on k-receptors is associated with diuresis and suppression of plasma vasopressin levels. The antidiuresis seen after high doses may be due to its activity on μ-receptors, possibly at a central site.
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