Chemical capture of wild swamp buffalo (Bubalus bubalis) in tropical northern Australia using thiafentanil, etorphine and azaperone combinations.

BACKGROUND: Studying wild animals in situ is fundamental to collecting baseline information, but generally they need to be immobilised for examination, sampling, marking and/or equipping with tracking apparatus. Capturing wild animals is inherently risky and there is a need for immobilisation methods that are safe for both the animals and researchers. METHODS: A total of 16 free-ranging swamp buffalo (Bubalus bubalis) were chemically captured by dart for the application of satellite tracking collars in tropical northern Australia; 7 animals were anesthetised with a thiafentanil-etorphine-azaperone (TEA) combination and 9 animals with a thiafentanil-azaperone (TA) combination. Anaesthesia was reversed with intravenous naltrexone. Mean dosages of etorphine and thiafentanil for animals in the TEA group were 0.01 mg/kg of each drug and mean dosage of thiafentanil for animals in the TA group was 0.02 mg/kg. Total dose per animal of azaperone and naltrexone was 80 mg and 150 mg, respectively. Anaesthetic monitoring was by physical observation of physiological variables, pulse oximetry and capnography. Blood laboratory parameters including creatine kinase (CK), aspartate transaminase (AST), serum bicarbonate and anion gap were measured. RESULTS: All subject animals recovered well from anaesthesia despite the occurrence of subclinical acidosis in some patients. There was no significant difference between the treatment groups. Conversely, chase time had an adverse effect on body temperature, irrespective of the anaesthetic combination used. CONCLUSIONS: Thiafentanil and azaperone, with or without etorphine, delivered rapid safe, effective, reversible field anaesthesia in healthy swamp buffalo.

Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist.

BACKGROUND AND PURPOSE: The opioid receptor family comprises four structurally homologous but functionally distinct sub-groups, the µ (MOP), δ (DOP), κ (KOP) and nociceptin (NOP) receptors. As most opioid agonists are selective but not specific, a broad spectrum of behaviours due to activation of different opioid receptors is expected. In this study, we examine whether other opioid receptor systems influenced KOP-mediated antinociception. EXPERIMENTAL APPROACH: We used a tail withdrawal assay in C57Bl/6 mice to assay the antinociceptive effect of systemically administered opioid agonists with varying selectivity at KOP receptors. Pharmacological and genetic approaches were used to analyse the interactions of the other opioid receptors in modulating KOP-mediated antinociception. KEY RESULTS: Etorphine, a potent agonist at all four opioid receptors, was not anti-nociceptive in MOP knockout (KO) mice, although etorphine is an efficacious KOP receptor agonist and specific KOP receptor agonists remain analgesic in MOP KO mice. As KOP receptor agonists are aversive, we considered KOP-mediated antinociception might be a form of stress-induced analgesia that is blocked by the anxiolytic effects of DOP receptor agonists. In support of this hypothesis, pretreatment with the DOP antagonist, naltrindole (10 mg·kg(-1) ), unmasked etorphine (3 mg·kg(-1) ) antinociception in MOP KO mice. Further, in wild-type mice, KOP-mediated antinociception by systemic U50,488H (10 mg·kg(-1) ) was blocked by pretreatment with the DOP agonist SNC80 (5 mg·kg(-1) ) and diazepam (1 mg·kg(-1) ). CONCLUSIONS AND IMPLICATIONS: Systemic DOP receptor agonists blocked systemic KOP antinociception, and these results identify DOP receptor agonists as potential agents for reversing stress-driven addictive and depressive behaviours mediated through KOP receptor activation. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2.

TH-030418: a potent long-acting opioid analgesic with low dependence liability.

Numerous efforts have been made on the chemical modification of opioid compounds, with the ultimate goal of developing new opioid analgesics that is highly potent and low/non-addictive. In a search for such compounds, TH-030418 [7α-[(R)-1-hydroxy-1-methyl-3-(thien-3-yl)-propyl]-6,14-endo-ethanotetrahydrooripavine] was synthesized. Here, we evaluated the pharmacological activities of TH-030418, in comparison with morphine, the prototype opioid analgesic. In radioligand binding assays, TH-030418 bound potently and nonselectively to µ-, δ-, κ-, and ORL1 (opioid receptor-like 1) receptors stably expressed in CHO (Chinese hamster ovary) cells with K (i) values of 0.56, 0.73, 0.60, and 1.55 nM, respectively. When administered subcutaneously, TH-030418 was much more potent than morphine in analgesia, with the ED(50) values of 1.37 µg/kg and 1.70 µg/kg in hot plate and acetic acid writhing tests, respectively. The opioid antagonist naloxone blocked the antinociceptive effect of TH-030418, indicating that the action of TH-030418 was mediated by opioid receptors. The antinociceptive effect of s.c. TH-030418 in hot plate test lasted for more than 12 h, which is much longer than those of morphine (2.5 h) and dihydroetorphine (1.5 h). In addition, naloxone did not precipitate withdrawal syndrome in the mice treated with TH-030418 previously. Most importantly, TH-030418 did not induce conditioned place preference in mice after chronic treatment. These results indicate that TH-030418 is a potent long-acting opioid analgesic with low dependence liability and may be of some value in the development of new analgesics.

Dihydroetorphine: a potent analgesic: pharmacology, toxicology, pharmacokinetics, and clinical effects.

Dihydroetorphine (DHE) is one of the strongest analgesic opioid alkaloids known; it is 1000 to 12000 times more potent than morphine. Several in vitro and in vivo studies have shown that DHE is a selective mu-opioid receptor (OP(3)) agonist that also binds and activates all human recombinant mu-, delta-, and kappa-opioid receptors (OP(3), OP(1), and OP(2)). The onset of the analgesic effect of DHE in rodents is rapid, 5 to 15 min after parenteral administration; the duration of action is short, the analgesic effect disappears within 120 min after administration. By oral administration much higher doses of DHE are required to produce analgesic effects. These characteristics are accounted for by the pharmacokinetic properties of DHE in the rat, namely, by rapid distribution of DHE from the injection site to the brain and rapid metabolism by glucuronidation in the gut and liver followed by elimination into the bile. Continuous infusion and repeated administration of DHE lead to the development of tolerance to analgesia, physical dependence, and a rewarding effect in normal rats but not in animals with formalin-induced inflammation. Although formalin-induced inflammation is only one type of pain stimulus, these findings suggest that DHE addiction would be observed only in the case of pain-free conditions. Clinical reports in China show that sublingual doses of DHE, 20 to 180 microg, produce a potent analgesic effect with only mild side effects, including dizziness, somnolence, nausea, vomiting, constipation, and shortness of breath. To improve the short-lasting effect following sublingual administration, transdermal delivery of DHE via a patch has been investigated. The patch formulation of DHE produces continuous analgesic effect with minimal physical dependence and rewarding effect in rats suffering from chronic pain. This patch formulation, which is very suitable for DHE, may be viable for the treatment of severe pain and is likely to improve patients' quality of life.

Anti-allodynic actions of intravenous opioids in the nerve injured rat: potential utility of heroin and dihydroetorphine against neuropathic pain.

Neuropathic pain has been suggested to be resistant to treatment with opiates. Such perceived lack of opioid responsiveness may be due to the dose-range over which specific opioid compounds have been studied as well as the efficacy of these compounds. Dihydroetorphine is a novel opiate that demonstrates significantly greater analgesic potency compared to morphine, and which also demonstrates diminished capacity for producing physical dependence in laboratory animals. The present study compared the intravenous (i.v.) efficacy, potency and duration of action of dihydroetorphine, fentanyl, heroin and morphine in producing anti-allodynic actions in a rat model of neuropathic pain (ligation of the L5/L6 nerve roots). All compounds produced significant anti-allodynic activity with dihydroetorphine being the most potent (A50 of 0.2 microg kg(-1), i.v.). Morphine was approximately 7440 times less potent than dihydroetorphine while heroin and fentanyl were approximately 163.5 and 6.9 times less potent in producing anti-allodynic actions. Dihydroetorphine also showed a maximal effect at 0.6 microg kg(-1) in all animals tested, while 100 microg kg(-1) was required for heroin to produce a maximal effect. Fentanyl and morphine did not elicit a maximum anti-allodynic response (74 and 76% maximum possible effect (%MPE), respectively). As expected, fentanyl showed a relatively brief duration of action (approximately 20 min at the highest tested dose), while dihydroetorphine and morphine demonstrated anti-allodynic actions for up to 45 min. Heroin had the longest duration of action, producing significant anti-allodynic effects for up to 90 min. These data show that dihydroetorphine and heroin produce potent and long-lasting anti-allodynic actions in this model. Additionally, in contrast to morphine and fentanyl, both dihydroetorphine and heroin were able to achieve a maximal response. The remarkable potency, maximal efficacy and duration of action of these compounds, particularly dihydroetorphine, suggests that these compounds may warrant further examination as potential therapeutic treatments for neuropathic pain states.

[Colonic dialysis therapy of Chinese herbal medicine in abstinance of heroin addicts--report of 75 cases].

OBJECTIVE: To observe the efficacy of the colonic dialysis therapy of Chinese medicine in abstinance of heroin addicts. METHODS: One hundred and twenty five cases of heroin addicts were randomly divided into two groups: group A was treated with combined dihydroetorphine (DHE) and methadon therapy; group B, besides DHE and methadon, the addicts were given colon dialysis with Chinese herbal medicine from third day of the treatment through to the eighth day. RESULTS: The effect of group B was superior to that of group A in that the patients heroin abstinance symptoms disappeared more rapidly, the course of the disease was shorter and the effective rate raised to 100%. CONCLUSION: The cutaneous pigmentation could be removed through dialysis quickly which suggested that the method was able to remove toxic substances in the body and it would benefit the abstinance of heroin addicts.

[Clinical study on painless labor under drugs combined with acupuncture analgesia].

To study the analgesia efficacy of drugs combined with acupuncture analgesia for painless labor, 462 normal pregnancy women were observed. During the latent phase in labor, several analgesia methods: acupuncture analgesia, analgesics, magnetotherapy and auricular acupressure, TENS combined with dihydroetorphine were used respectively. While the intrauterine pressure and the peripheral content of beta-EP were measured during labor, the experiments of SEPS were also performed on healthy adults to demonstrate the analgesia efficacy of those analgesia methods. The combination of drugs with acupuncture is an excellent method for painless labor without any complications and all the mothers and babies are safety. The effectiveness is 97.5%. The results demonstrate that the mechanism of analgesia efficacy should be regulated the incoordinate uterine action and improve the hypertonic status of uterus, but also can decrease the pain threshold and elevate the tolerance of uterine contractions during labor.

Antitussive effect of dihydroetorphine in mice.

The present study examined the opioid receptors involved in the antitussive effect of dihydroetorphine in mice. Dihydroetorphine suppressed coughs dose dependently at doses between 0.1-1 micrograms/kg i.p. Blockade of mu-opioid receptors by pretreatment with beta-funaltrexamine significantly reduced the antitussive effect of dihydroetorphine. Furthermore, the antitussive effect of dihydroetorphine was also antagonized by nor-binaltorphimine, a kappa-opioid receptor antagonist. However, pretreatment with naltrindole, a delta-opioid receptor antagonist, did not affect the antitussive effect of dihydroetorphine. These results indicate that the antitussive effect of dihydroetorphine is mediated by the activation of mu-opioid receptors and of kappa-opioid receptors, but not delta-opioid receptors.

[Clinical assessment of physical dependence potential of dihydroetorphine hydrochloride (DHE)].

This paper reports the DHE substitution clinical trial in 38 heroin addicts. The CINA (Clinical Institute Narcotic Assessment) scale was used to assess physical dependence potential. The CINA scale contains 10 opioid withdrawal signs (nausea, vomiting, gooseflesh, sweating, restlessness, tremor, larcrimation, nasal congestion, yawning, changes in heart rate and systolic blood pressure) and 3 opiate withdrawal symptoms (abdominal pain, muscle pain and feeling hot or cold). For each subject admitted to the Drug Detoxification and Treatment Center his (her) status on each of the 13 items of CINA were immediately rated. Then, naloxone 0.4 mg was injected iv to precipitate withdrawal symptoms and at 5, 10, 15 min after the naloxone injection, the CINA score of each patient was rated again. The differences among the scores of pre- and post-naloxone injection is a measurement of the degree of withdrawal symptoms. Then, a single dose of DHE was administered sublingually to each patient, all withdrawal symptoms disappeared. These results show that DHE can compete with naloxone for opioid receptors. A good dose-response relationship was found between the 100% suppressive withdrawal sign doses of DHE and the degree of withdrawal sign in heroin addicts. The physical dependence potential of DHE given to heroin addicts sublingually was probably more than that of methadone given to heroin addicts orally by making reference to the report of Dr. Peachy.

[Dihydroetorphine hydrochloride for moderate and severe cancer pain].

One hundred and three patients with moderate and severe cancer pain were given a sublingual analgesic agent--dihydroetorphine hydrochloride (DHE). Relief of cancer pain was moderate or complete in 89.3% (92/103). The average relief time (ART) was 3.9 hours and the average time before effectiveness was 20 minutes. In patients with acute or chronic cancer pain, moderate and complete pain-relief rates were 91.3% and 82.2% (P = 0.237). Difference of ART between them was insignificant (P = 0.299). The main clinical side-effects were somnolence (60%), dizziness (72%), nausea (30%), vomiting (16.5%), constipation (5%) and shortness of breath (8%). In two of the patients, the administration of DHE had to be stopped due to its side-effects. Age, sex and site of cancer pain were not related to the analgesic effects of DHE, but the pain-relief in patients with bladder cancer was poor (P less than 0.001). Within certain range, increase in dose was able to enhance its analgesic effect (P less than 0.001) and reduce drug resistance (P less than 0.001).

A double-blind clinical trial of the analgesic effects of R & S 218-M, a new potent analgesic for the relief or pain following abdominal surgery: comparison with morphine sulphate.

The analgesic effects of R & S 218-M, administered in doses of 0.56 mg/70 kg and 0.35 mg/70 kg, were compared with those of morphine sulphate 10.5 mg/70 kg for the relief of abdominal pain following surgery in healthy adults. The drugs were given as the first potent analgesic after operation and the subjects were interviewed at 30-min intervals until the pain became severe again. All the interviews were conducted by the one observer. R & S 218-M 0.56 mg/70 kg was as effective as morphine sulfate 10.5 mg/70 kg, while R & S 218-M 0.35 mg/70 kg was inferior. No evidence was found to support the claim that R & S 218-M causes less respiratory depression when compared with morphine sulphate.