Centrally and peripherally mediated inhibition of intestinal motility by opioids

Abstract

Intracerebroventricularly injected morphine is 50-fold more potent in arresting intestinal peristalsis in rats, mice or guinea pigs than morphine administered systemically. Using quaternary naloxone as narcotic antagonist, it has been demonstrated that the peripheral pathway of the centrally mediated constipatory effect of morphine does not involve opioid peptidergic mechanisms. Further, this effect is not due to the release of opioid peptides from the pituitary, since hypophysectomy fails to affect the antipropulsive activity of morphine. On the other hand, the intestinal motility can be affected directly by activation of opiate receptors located in the gut. This was best demonstrated with loperamide, which exhibits predominantly a peripheral site of action. Thus, two mechanisms of the action of morphine on gastrointestinal propulsive activity have been demonstrated. One arises in the central nervous system (CNS) and is mediated peripherally not by opioid peptidergic pathways, whereas the other is due to a direct action of morphine on the gut.

Effects of Enkephalins and Morphine on Spontaneous Electrical Activity and on Junction Potentials Elicited by Parasympathetic Nerve Stimulation in Cat and Rabbit Colon

“…This reduction in intramural neurone discharge has been confirmed by intracellular recordings in myenteric neurones of the intestine of both guinea-pig (North & Tonini, 1977;Morita & North, 1981) and cat (Wood, 1980). Morphine has also an indirect effect on the motility of small intestine by acting on the central nervous system (Stewart, Weisbrodt & Burks, 1976;Schulz, Wuster & Herz, 1979;Pascaud, Genton, Remond & Vincent, 1980;Weisbrodt, Thor, Anderson & Copeland, 1981). …”

Design and Synthesis of a Piperidinone Scaffold as an Analgesic through Kappa-Opioid Receptor: Structure–Activity Relationship Study of Matrine Alkaloids

“…After being stirred at rt for 10 h, the reaction mixture was alkalized with 10% aqueous NaOH, and extracted with CH 2 Cl 2 . The organic layer was dried over anhydrous Na 2 SO 4 (1-N-Benzylpiperidin-4-ylidene)acetonitrile (15) Potassium carbonate (3.65 g, 26.4 mmol) was added to a solution of diethyl cyanomethanephosphonate (4.97 mL, 31.7 mmol) in tetrahydrofuran (THF) (6 mL) under nitrogen atmosphere. The reaction mixture was stirred at rt for 15 min, warmed to reflux for 20 min.…”

“…The syntheses of 5a and b began with N-benzylation of commercially available 4-carboxamidopiperidine (11). Amide 12 was converted to the amine by reduction with LiAlH 4 , 16) and treated with HCHO and HCO 2 H to yield 13. After debenzylation using Pd(OH) 2 , acylation of the secondary amine gave the target compounds 5a and b.…”

“…11) Although intracerebroventricular pretreatment with an antiserum against dynorphin A (1-17) did not affect the antinociceptive effect induced by subcutaneous (s.c.) treatment of 1 and 2, the antinociceptive effect was greatly attenuated by intrathecal (i.t.) pretreatment with an antiserum against dynorphin A (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) in mice. This suggested that the antinociceptive effect induced by s.c. treatment of 1 and 2 occurred without binding to the KOR in the ventricles of the brain, in where might stimulate the descending dynorphinergic neuron and production of dynorphin in the spinal cord.…”

“…[12][13][14] We hypothesized that the level of the antinociceptive effect would be affected by the distance between the amide and amino groups, which are important structural components of compound 3. To investigate this, model compounds (4)(5)(6) were designed to study the effect of the spatial relationship between the amide and amine groups on the agonistic activity (Fig. 2).…”