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Opioid-induced constipation (OIC), a typical side effect of opioids, is due to activation of the μ-opioid receptors in the enteric nervous system. Peripherally acting μ-opioid receptor antagonists (PAMORAs) can reverse OIC by inhibiting the peripheral action of opioids without affecting centrally mediated analgesia. Naldemedine is a PAMORA with potent antagonist activity against μ-, δ-, and κ-opioid receptors. In this study, the pharmacological profiles of naldemedine, compared with those of naloxone and naloxegol, were evaluated. In vitro, Schild plot analysis indicated that naldemedine was a noncompetitive antagonist of μ-opioid receptors, whereas other compounds were competitive antagonists. Also, naldemedine showed slower association and dissociation kinetics than the other compounds. In vivo, naldemedine dose-dependently ameliorated morphine-induced inhibition of small intestinal transit (SIT). The dose-response curve was not shifted at 1 and 3 mg/kg morphine. On the contrary, that of naloxegol was significantly shifted to the right from 1 to 3 mg/kg morphine. In morphine-dependent rats, naldemedine caused peripheral withdrawal symptoms (diarrhea) at doses higher than 1 mg/kg, whereas the dose that produced half the maximal preventive effect (ED50) against constipation was 0.03 mg/kg. Naldemedine showed slower onset and a lesser severity of diarrhea than the other compounds at close to the ED50 value in the SIT model. Our results reveal that naldemedine has different pharmacological profiles (type of antagonism and binding kinetics) to the other compounds. This might explain the differential inhibition of morphine-induced SIT and withdrawal symptoms among the three antagonist compounds. SIGNIFICANCE STATEMENT: Naldemedine is a novel peripherally acting μ-opioid receptor antagonist with potent antagonist activity against μ-, δ-, and κ-opioid receptors. Naldemedine showed a noncompetitive antagonism and slower association and dissociation kinetics against μ-opioid receptors than naloxone and naloxegol. Naldemedine showed insurmountable antagonism of morphine-induced inhibition and lower and slower peripheral withdrawal symptoms (diarrhea) than the other compounds. Therefore, naldemedine has a different pharmacological profile (the type of antagonism and binding kinetics) to the other compounds.

Structure-activity relationship studies of several morphinan derivatives were conducted to obtain dual antagonists for μ- and δ-opioid receptors. We discovered peripherally restricted dual antagonists for μ/δ-opioid receptors as a new chemotype with a morphinan scaffold, which are orally available and do not easily pass the blood–brain barrier. As we expected, some of these compounds inhibit opioid-induced constipation and emesis/vomiting with limited potential to interfere the analgesic effects of morphine. Among them, naldemedine was selected as a potential drug candidate.

Naloxone is a μ-opioid receptor antagonist that has been used to prevent overdose-related respiratory depression and deaths by the illicit use of opioids. Naloxone can also deter the abuse potential of opioids, but little has been reported regarding its antagonistic activity profile against opioid-induced psychological dependence. This study aimed to confirm the antagonistic activity profile of naloxone against several μ-opioid receptor agonists and investigate whether naloxone could affect the psychological dependence induced by widely used μ-opioid receptor agonist, oxycodone. In the Guanosine-5’-o-(3-thio) triphosphate (GTPγS) binding assay, naloxone (30−30,000 nM) inhibited the GTPγS binding induced by oxycodone, hydrocodone, morphine, and fentanyl. It elicited parallel rightward shifts in the concentration-response curves, indicating that naloxone possessed a competitive antagonistic activity profile against these μ-opioid receptor agonists. In the conditioned place preference test, oxycodone (0.01−1 mg/kg, i.v.) produced dose-dependent increases in place preference. The increased place preference induced by oxycodone (1 mg/kg) was significantly attenuated by co-administration of naloxone at a dose of 0.5 mg/kg but not 0.01 mg/kg. Naloxone (0.5 mg/kg, i.v.) also blocked oxycodone (1 mg/kg)-induced dopamine release in nucleus accumbens; however, at a lower dose (0.01 mg/kg), it did not affect the intrinsic dopamine release by oxycodone. These results indicate that the psychological dependence of oxycodone could be antagonized by naloxone, depending on the dose. This characterization might lead to a better understanding of the competitive antagonistic activity profile of naloxone for μ-opioid receptor in the brain.

Opioid-induced constipation (OIC), a typical side effect of opioids, is due to activation of the

Background Naldemedine (S‐297995) is a peripherally acting μ‐opioid receptor antagonist developed as a once‐daily oral drug for opioid‐induced constipation (OIC) in adults with chronic noncancer or cancer pain. This study characterized the pharmacological effects of naldemedine in vitro and in vivo. Methods The binding affinity and antagonist activity of naldemedine against recombinant human μ‐, δ‐, and κ‐opioid receptors were assayed in vitro. Pharmacologic effects of naldemedine were investigated using animal models of morphine‐induced inhibition of small and large intestinal transit, castor oil‐induced diarrhea, antinociception, and morphine withdrawal. Key Results Naldemedine showed potent binding affinity and antagonist activities for recombinant human μ‐, δ‐, and κ‐opioid receptors. Naldemedine significantly reduced opioid‐induced inhibition of small intestinal transit (0.03‐10 mg kg−1; P, Naldemedine displayed potent binding affinity to, and antagonistic activity against, μ‐, δ‐, and κ‐opioid receptors. Naldemedine tempered OIC in vivo without compromising opioid analgesia.

Aims Naldemedine is a peripherally acting μ-opioid receptor antagonists (PAMORAs) indicated for the treatment of opioid-induced constipation (OIC). We investigated the preventive effect of naldemedine on morphine-induced nausea and vomiting in ferrets and conducted a pharmacokinetic/pharmacodynamic (PK/PD) analysis. Main methods The antiemetic effect of naldemedine was evaluated as the frequency and time of retching (rhythmic abdominal contractile motion) and vomiting (throwing up vomit or similar reactions) caused by morphine in ferrets. After a single oral administration of naldemedine to ferrets, the plasma concentrations of naldemedine and morphine were measured by liquid chromatography–tandem mass spectrometry. Key findings Naldemedine showed a potent and dose-dependent anti-emetic effects against morphine-induced emetic responses, for up to 6 h. The dose of naldemedine that produced half the maximal effect (ED50) value for anti-emetic effect of naldemedine in the morphine-treated ferrets was 0.033 mg/kg. The PK/PD analysis revealed that the antiemetic effect was related to the plasma naldemedine concentration, with a half maximal effective concentration that produces half the maximal effect (EC50) of 3.51 ng/mL. The plasma concentration producing an antiemetic effect was almost 200-fold lower than that inducing an anti-analgesic effect in rats. Significance Naldemedine showed potent inhibition of morphine-induced vomiting for up to 6 h after dosing. These data suggest that naldemedine possesses antiemetic properties and could be effective against opioid-induced nausea and vomiting (OINV).

Oxaliplatin is a chemotherapeutic agent that induces chronic refractory neuropathy. To determine whether opioids effectively relieve this chronic neuropathy, we investigated the efficacies of morphine, oxycodone, and fentanyl, and the mechanisms underlying opioid antinociception, in oxaliplatin-induced neuropathy in rats. Rats exhibited significant mechanical allodynia following 2 weeks of chronic oxaliplatin administration. Within the range of doses that did not induce sedation and/or muscle rigidity, morphine (3 mg/kg, subcutaneously, s.c.) and oxycodone (0.3 – 0.56 mg/kg, s.c.) completely reversed oxaliplatin-induced mechanical allodynia, whereas fentanyl (0.017 – 0.03 mg/kg, s.c.) showed partial antinociception. The antinociception of the optimal doses of morphine and oxycodone were completely inhibited by pertussis toxin (PTX; 0.5 μg/rat, i.c.v.), a Gi/o protein inhibitor, while the partial effect of fentanyl was not affected in the oxaliplatin model. In the [35S]-GTPγS binding assay, activation of μ-opioid receptor by fentanyl, but not by morphine or oxycodone, in the mediodorsal thalamus was significantly reduced in oxaliplatin-treated rats. These results indicate that the lower antinociceptive potency of fentanyl in the oxaliplatin model might in part result from the loss of PTX-sensitive Gi/o protein activation, and the degree of Gi/o protein activation might be related to the potency of antinociception by opioids in this model. Keywords:: opioid, antinociception, oxaliplatin, neuropathy, Gi/o protein

The rewarding effects of μ-receptor agonists can be suppressed under several pain conditions. We recently showed that clinically used μ-receptor agonists possess efficacies for relieving the neuropathic pain induced by chemotherapeutic drug in rats; however, it is possible that the use of μ-receptor agonists may trigger the rewarding effects even under chemotherapeutic drug–induced neuropathic pain. Nevertheless, no information is available regarding whether μ-receptor agonists produce psychological dependence under chemotherapeutic drug–induced neuropathic pain. Therefore, we examined the effects of neuropathy induced by chemotherapeutic drugs on the rewarding effects of morphine, oxycodone, and fentanyl in rats. Repeated treatment with oxaliplatin or paclitaxel produced neuropathy as measured by the von Frey test. Rewarding effects produced by antinociceptive doses of μ-receptor agonists were not suppressed under oxaliplatin- or paclitaxel-induced neuropathy. Furthermore, the morphine-induced increase in the release of dopamine from the nucleus accumbens, which is a critical step in the rewarding effects of μ-receptor agonists, was not altered in paclitaxel-treated rats. These results suggest that the rewarding effects of μ-receptor agonists can still be established under oxaliplatin- or paclitaxel-induced neuropathic pain. Therefore, patients should be carefully monitored for psychological dependence on μ-receptor agonists when they are used to control chemotherapeutic drug-induced neuropathic pain. Keywords:: rewarding effect, oxaliplatin, paclitaxel, neuropathic pain, μ-opioid receptor agonist

Although norepinephrine transporter (NET) inhibition has an additional effect on μ-opioid receptor (MOR)-mediated anti-nociception in inflammatory and neuropathic pain, its effect on cancer pain is not well characterized. We investigated the additional effect of NET inhibition on MOR activation using a mouse femur bone cancer (FBC) pain model by comparing the antinociceptive effect of the dual-acting opioids tramadol and tapentadol and the clinically used MOR-targeted opioids oxycodone and morphine. The anti-nociceptive effects of subcutaneously administered opioids were assessed using the von-Frey filament test. Oxycodone (1 – 10 mg/kg) and morphine (5 – 50 mg/kg) dose-dependently exhibited potent anti-nociceptive effects, whereas tramadol (10 – 56 mg/kg) and tapentadol (10 – 30 mg/kg) exhibited partial effects. Rota-rod analyses of tapentadol at a higher dose (> 30 mg/kg) showed a significant decrease in motor coordination, which was partially recovered by pretreatment with MOR or α1-adrenoceptor antagonists. The partial anti-nociceptive effect of tapentadol (30 mg/kg) was completely suppressed by a MOR antagonist, but not by α1- or α2-adrenoceptor antagonists, suggesting that neither α1-adrenoceptor- nor α2-adrenoceptor-mediated pathways are involved in anti-nociception in the FBC model. We conclude that addition of NET inhibition does not contribute to MOR-mediated anti-nociception in bone cancer pain. Keywords:: femur bone cancer pain, norepinephrine transporter, oxycodone, tapentadol, μ-opioid receptor (MOR)

In addition to pain sensation, both thermal regulation and thermosensation are thought to be influenced by TRPV1 channel functioning. Involvement of TRPV1 in these latter physiological functions became clear during pharmaceutical development of selective TRPV1 antagonists for the treatment of chronic painful conditions. The majority of TRPV1 antagonists that have been progressed into clinical trials were reported to increase body temperature (hyperthermia) in healthy humans. Currently, hyperthermia is a major concern in pharmaceutical development of TRPV1 antagonists. We therefore sought of an in-vitro method to identify compounds with a low hyperthermic potential early in the drug discovery process. Using whole-cell patch clamp electrophysiology on human TRPV1 expressing CHO cells, we performed kinetic measurements of dissociation from the receptor of known hyperthermic (AMG517 and ABT102) and non-hyperthermic (SB705498) TRPV1 antagonists. We found that AMG517 and ABT102, two hyperthermic compounds, exhibited slow off- (dissociation) rates when channels were activated by capsaicin. Conversely, the non-hyperthermic compound SB705498, showed a significantly faster rate of dissociation from the receptor. Finally, we assessed an in-house proprietary antagonist V116517 which demonstrated significant separation between analgesic efficacy and hyperthermia. Once again, this compound displayed a faster off-rate as compared to the hyperthermic compounds.With these initial findings we hypothesize that the dissociation rate of an antagonist from the TRPV1 channel is an important parameter in determining a compound's effect on thermal regulation and thermosensation. Antagonists with a fast off-rate may allow endogenous ligands to interact with the TRPV1 channel and thereby fulfil its physiological role in body temperature regulation while still effectively modifying pain signaling. In conclusion, our findings suggest that in vitro kinetic measurements early in the drug discovery process may be a useful means of identifying non-hyperthermic TRPV1 antagonists.

Morphine, oxycodone, and fentanyl are clinically prescribed drugs for the management of severe pain. We investigated whether these opioids possess different efficacy profiles on several types of pain in mouse pain models. When the three opioids were tested in the femur bone cancer model, all of them significantly reversed guarding behavior, whereas the effects on limb-use abnormality and allodynia-like behavior differed among the opioids. Particularly, although oxycodone (5 – 20 mg/kg) and fentanyl (0.2 mg/kg) significantly reversed limb-use abnormality, not even a high dose of morphine (50 mg/kg) could reverse it. When the effects of these opioids were examined in a sciatic nerve ligation (SNL) model of neuropathic pain, oxycodone was the most effective, producing an antinociceptive effect without affecting the withdrawal threshold of sham-treated animals. When the effects of these opioids were examined with the tail-flick test using naive animals, oxycodone, morphine, and fentanyl exhibited antinociceptive effects on thermal nociception. These results show that the three opioids exhibit different efficacy outcomes in multiple pain models and that the efficacy profile of oxycodone does not overlap those of morphine and fentanyl. Keywords:: oxycodone, morphine, fentanyl, neuropathic pain-like state, bone cancer pain

Porcine pancreatic group I phospholipase A2 (PLA2-I) induced contraction of guinea pig lung parenchyma in a concentration-dependent manner. Its EC50 value was similar to theKd value calculated from the specific binding of125I-labeled porcine PLA2-I in the membrane fraction of guinea pig lung. Type-specific action of PLA2's and homologous desensitization strongly implicated the involvement of PLA2-I-specific sites in the activation process. Throm☐ane A2 was found to be the main product from lung tissue by PLA2-I action and the contractile response by PLA2-I was specifically suppressed by throm☐ane A2 receptor antagonists and cyclooxygenase inhibitor, but not by leukotriene receptor antagonist and H1 blocker. These findings indicate that PLA2-I-induced contractile response may depend on the secondarily produced throm☐ane A2, thus providing a new aspect of PLA2-I from the pathophysiological standpoint.