Radiographic dose-dependency study of loperamide effects on gastrointestinal motor function in the rat. Temporal relationship with nausea-like behavior

Loperamide is a potent mu opioid receptor agonist available over the counter to treat diarrhea. Although at therapeutic doses loperamide is devoid of central effects, it may exert them if used at high doses or combined with drugs that increase its systemic and/or central bioavailability. Recently, public health and scientific interest on loperamide has increased due to a growing trend of misuse and abuse, and consequent reports on its toxicity. Our aim was to evaluate in the rat the effects of increasing loperamide doses, with increasing likelihood to induce central effects, on gastrointestinal motor function (including gastric dysmotility and nausea-like behavior). Methods: Male Wistar rats received an intraperitoneal injection of vehicle or loperamide (0.1, 1, or 10 mg kg). Three sets of experiments were performed to evaluate: (a) central effects (somatic nociceptive thresholds, immobility time, core temperature, spontaneous locomotor activity); (b) general gastrointestinal motility (serial X-rays were taken 0-8 hours after intragastric barium administration and analyzed semiquantitatively, morphometrically, and densitometrically); and (c) bedding intake (a rodent indirect marker of nausea). Animals from sets 1 and 3 were used to evaluate gastric dysmotility ex vivo at 2 and 4 hours after administration, respectively. Key Results: Loperamide significantly induced antinociception, hypothermia, and hypolocomotion (but not catalepsy) at high doses and dose-dependently reduced gastrointestinal motor function, with the intestine exhibiting higher sensitivity than the stomach. Whereas bedding intake occurred early and transiently, gastric dysmotility was much more persistent. Conclusions and inferences: Our results suggest that loperamide-induced nausea and gastric dysmotility might be temporally dissociated.Ministerio de Ciencia e Innovación (SAF2012‐40075‐C02‐01)

Opioid peptide-derived analgesics

Two recent developments of opioid peptide-based analgesics are reviewed. The first part of the review discusses the dermorphin-derived, cationic-aromatic tetrapeptide H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA, where Dmt indicates 2′,6′-dimethyltyrosine), which showed subnanomolar μ receptor binding affinity, extraordinary μ receptor selectivity, and high μ agonist potency in vitro. In vivo, [Dmt1]DALDA looked promising as a spinal analgesic because of its extraordinary antinociceptive effect (3000 times more potent than morphine) in the mouse tail-flick assay, long duration of action (4 times longer than morphine), and lack of effect on respiration. Unexpectedly, [Dmt1]DALDA also turned out to be a potent and long-acting analgesic in the tail-flick test when given subcutaneously (s.c.), indicating that it is capable of crossing the blood-brain barrier. Furthermore, little or no cross-tolerance was observed with s.c. [Dmt1]DALDA in morphine-tolerant mice. The second part of the review concerns the development of mixed μ agonist/δ antagonists that, on the basis of much evidence, are expected to be analgesics with a low propensity to produce tolerance and physical dependence. The prototype pseudopeptide H-Dmt-TicΨ[CH2NH]Phe-Phe-NH2 (DIPP-NH2[Ψ], where Tic indicates 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) showed subnanomolar μ and δ receptor binding affinities and the desired μ agonist/δ antagonist profile in vitro. DIPP-NH2[Ψ] produced a potent analgesic effect after intracerebroventricular administration in the rat tail-flick assay, no physical dependence, and less tolerance than morphine. The results obtained with DIPP-NH2[Ψ] indicate that mixed μ agonist/δ antagonists look promising as analgesic drug candidates, but compounds with this profile that are systemically active still need to be developed