Weak Analgesia Research Articles

Research and development of κ opioid receptor agonists and δ opioid receptor agonists.

Delta opioid delta receptor (DOP) agonists were expected to be analgesics and many researchers tried to develop the SNC80 derivatives. However, the derivatives were dropped at the stage of early clinical trials because of undesirable side effects and weak analgesia. On the other hand, DOP agonists have been proposed as attractive candidates for the novel psychotropic drugs. We recently succeeded in synthesizing a novel selective DOP agonist KNT-127. KNT-127 produced neither catalepsy nor convulsive effects. We have demonstrated that KNT-127 has potent anxiolytic-like effect in rat models of innate anxiety. This anxiolytic-like effect was independent from known adverse effect of benzodiazepine, such as memory impairment, motor coordination deficits, and ethanol interactions. We have also demonstrated that KNT-127 showed potent and rapid antidepressant-like effects in rat models of depression. This antidepressant-like effect was independent from known adverse effect of selective serotonin reuptake inhibitor (SSRI), such as digestive symptoms. Therefore, we propose that DOP should be considered as an attractive target for the development of novel psychotropic drugs, without producing the adverse effects associated with benzodiazepine anxiolytics and SSRI antidepressants. Very recently, we developed another delta agonist NC-2800 with a different structure. NC-2800 is now in the preclinical stage using the CiCLE fund supported by AMED (Japanese Agency for Medical Research and Development).

Chronic adverse effects after axillary lymphadenectomy in breast cancer patients after weaker and stronger postoperative analgesia: Results of a prospective double-blind randomized study.

e23066 Background: Tramadol is commonly used for pain treatment, but it is not known if stronger postoperative analgesia has an effect on chronic adverse effects in breast cancer patients. The aim of this study was to compare the rate of chronic adverse effects after weaker and stronger postoperative analgesia. Methods: A prospective double-blind randomized study included 118 breast cancer patients receiving tramadol for pain relief after axillary lymphadenectomy from 2015 to 2018 (Study EUDRA CT: 2015-000992-28). All patients used one of two analgesic regimens for 4 weeks after lymphadenectomy. Patients with larger dose received 75/650 mg of tramadol with paracetamol every 8 hours and a group with lower dose received 37.5/325 mg of tramadol with paracetamol every 8 hours. All patients received for four weeks twice daily naproxen sodium 550 mg and once a day pantoprazole 20 mg. One year after surgery patients were evaluated for the presence of neuropathic pain, chronic pain, arm symptoms and lymphedema. The association between dose of tramadol and chronic postoperative adverse effects was evaluated using asymptotic z-test and chi-square test. Results: Neuropathic pain was more common one year in comparison to one month after lymphadenectomy (p = 0.0001). There was a trend for lower rate of neuropathic pain after stronger analgesia in comparison to weaker analgesia (p = 0.058). Chronic pain was present in 18% of patients one year after lymphadenectomy. There was no difference in rate of chronic pain after stronger and weaker postoperative analgesia. Patients had less arm symptoms after stronger analgesia than after weaker analgesia (p = 0.02). Furthermore, there was a trend for lower rate of lymphedema of forearm after stronger analgesia than after lower analgesia (p = 0.078). Conclusions: The patients who received stronger postoperative analgesia had a statistical trend for less often neuropathic pain in comparison to patients who received weaker analgesia. The patients who received stronger postoperative analgesia had less arm symptoms and better quality of life in comparison to patients who received weaker analgesia. Clinical trial information: EudraCT 2015-000992-28.

Pharmacological Properties of Novel Cyclic Pentapeptides with µ-opioid Receptor Agonist Activity

In our previous paper we have reported the synthesis and biological activity of a cyclic analog, Tyr-c(D-Lys- Phe-Phe-Asp)-NH2, based on endomorphin-2 (EM-2) structure. This analog displayed high affinity for the µ-opioid receptor, was much more stable than EM-2 in rat brain homogenate and showed remarkable antinociceptive activity after intracerebroventricular (i.c.v.) injection. Even more importantly, the cyclic analog elicited weak analgesia also after peripheral administration, giving evidence that it was able to cross, at least to some extent, the blood-brain barrier (BBB). Here we describe further modifications of this analog aimed at enhancing brain delivery by increasing lipophilicity. Two new cyclic pentapeptides, Tyr-c(D-Lys-D-1-Nal-Phe-Asp)-NH2 and Tyr-c(D-Lys-D-2-Nal-Phe-Asp)-NH2 (where 1-Nal=1- naphthyl-3-alanine, 2-Nal=2-naphthyl-3-alanine) were synthesized and evaluated in biological assays. Both analogs showed high µ-opioid receptor affinity and agonist activity and were stable in the rat brain homogenates. Unfortunately, the increase of lipophilicity was achieved at the expense of water solubility. The analog with D-2-Nal residue showed strong analgesic effect when given i.c.v. but could not be tested after intravenous (i.v.) administration where higher concentrations of the compound are required. However, this analog showed inhibitory effect on gastrointestinal (GI) motility in vivo, providing an interesting approach to the development of peripherally restricted agents that could be useful for studying gastrointestinal disorders in animal models.

Modification of morphine analgesia and tolerance by flumazenil in male and female rats

This study assessed the effect of the central benzodiazepine receptor antagonist, 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4 H-imidazo[1,5- a][1,4]benzodiazepine-3-carboxylic acid ethyl ester (flumazenil), on morphine-induced analgesia, locomotor effects, and development of tolerance in rats. The thermally evoked pain (tail flick) response was determined after acute and chronic intraperitoneal (i.p.) administration of morphine and flumazenil, alone and in combination. In acute studies, flumazenil induced weak analgesia unrelated to dose and sex, whereas morphine-induced analgesia was dependent on both dose and sex (male>female). Flumazenil dose-dependently enhanced the analgesic effect of morphine in female but not in male rats. Isobolographic analysis suggested synergism between flumazenil and morphine in female rats, but antagonism in male rats. Flumazenil-induced locomotor changes (alone and with morphine) were related to sex but not dose. Chronic coadministration of flumazenil with morphine enhanced analgesia and attenuated tolerance development in female rats. The findings suggest a possible role for flumazenil as an adjunct with opioids in acute and chronic pain therapy.

Influence of ω-conotoxin on morphine analgesia and withdrawal syndrome in rats

The effect of ω-conotoxin on opiate analgesia and withdrawal syndrome was investigated in rats. ω-Conotoxin given i.c.v. and i.p. caused weak analgesia in the tail-flick test. When the toxin (20 ng/rat) was given i.c.v. immediately before morphine (1.5 μg/rat i.c.v.) the resultant analgesic effect was additive. In contrast, the analgesia elicited by morphine (3 μg/rat i.c.v.) was greatly reduced after 24-h pretreatment with the toxin (20 ng/rat i.c.v.). The systemic administration of the toxin (10 μg/kg i.p.) did not affect morphine analgesia whether ω-conotoxin was coadministered with morphine (2.5 mg/kg i.p.) or was given 24 h before the opiate (5 mg/kg i.p.). ω-Conotoxin i.c.v. injected in morphine-dependent rats 15 min before naloxone challenge significantly attenuated the abstinence syndrome. On the contrary systemic administration of ω-conotoxin failed to suppress the morphine withdrawal syndrome. The present results suggest that ω-conotoxin affects both acute and chronic effects of morphine.