Concurrent bullatine A enhances morphine antinociception and inhibits morphine antinociceptive tolerance by indirect activation of spinal κ-opioid receptors.

ETHNOPHARMACOLOGICAL RELEVANCE: Bullatine A, a C20-diterpenoid alkaloid and one of the major effective ingredients in Aconiti brachypodi Radix (Xue-shang-yi-zhi-hao), can block pain hypersensitivity in a variety of rodent models through expression of spinal microglial dynorphin A. AIM OF THE STUDY: To assess the interaction between bullatine A and morphine on antinociception in acute nociception and pain hypersensitivity states, with the exogenous synthetic dynorphin A as a comparison MATERIALS AND METHODS: Spinal nerve ligation-induced neuropathic rats and naïve mice were used for assessing the acute and chronic interactions of bullatine A/dynorphin A with morphine. RESULTS: Single subcutaneous injection of bullatine A or dynorphin A(1-17) did not either alter formalin- and thermally (hot-plate and water immersion tests)-induced acute nociception or potentiate morphine antinociception in naïve mice. In contrast, bullatine A dose-dependently inhibited formalin-induced tonic pain with the efficacy of 54% inhibition and the half-effective dose of 0.9mg/kg. Concurrent bullatine A additively enhanced morphine antinociception. In neuropathic rats, the antinociceptive effects of multiple bidaily intrathecal injections of bullatine A and dynorphin A remained consistent over 13 days, whereas morphine produced progressive and complete tolerance to antinociception, which was completely inhibited by concurrent bullatine A and dynorphin A. A single intrathecal injection of bullatine A and dynorphin A immediately reversed established morphine tolerance in neuropathic rats, although the blockade was a less degree in the thermally induced mouse acute nociceptive tests. The inhibitory effects of bullatine A and dynorphin A on morphine tolerance were immediately and completely attenuated by intrathecal dynorphin A antibody and/or selective κ-opioid receptor antagonist GNTI. CONCLUSION: These results suggest that bullatine A produces antinociception without induction of tolerance and inhibits morphine antinociceptive tolerance, and provide pharmacological basis for concurrent bullatine A and morphine treatment for chronic pain and morphine analgesic tolerance.

Topical capsaicin-induced allodynia in unanesthetized primates: pharmacological modulation.

Topically administered capsaicin produces thermal allodynia, and this effect has been used to investigate pain transduction and its pharmacological modulation. This study investigated the parameters of topical capsaicin-induced thermal allodynia in unanesthetized rhesus monkeys and its pharmacological modulation by centrally acting compounds [a kappa-opioid agonist: (5alpha,7alpha,8beta)-(+)-N-methyl-N-(7-[1-pyrrolidinyl]-1-oxaspiro [4.5]dec-8-yl)-benzeneacetamide (U69,593); and noncompetitive N-methyl-d-aspartate (NMDA) antagonists: ketamine and MK-801 (dizocilpine)]. Rhesus monkeys (n = 4) were studied within the warm water tail withdrawal assay (20-s maximum latency), using thermal stimuli that are normally not noxious (38 and 42 degrees C). Capsaicin was applied topically on the tail (0.0013 and 0.004 M capsaicin solution on a 1-cm2 patch; 15-min contact). Topical capsaicin produced concentration-dependent thermal allodynia in both temperatures, robustly detected 15 to 90 min after topical capsaicin removal. A similar allodynic profile was observed with topical administration of the "endovanilloid" N-arachidonoyl-dopamine. The kappa-agonist U69,593 (0.01-0.1 mg/kg, s.c.) dose dependently prevented capsaicin (0.004 M)-induced allodynia in 38 and 42 degrees C, and the largest U69,593 dose also reversed ongoing allodynia within this model. Two NMDA antagonists, ketamine and MK-801 (0.32-1.8 and 0.032-0.056 mg/kg, respectively), also prevented capsaicin-induced allodynia in 38 degrees C, but only variably in 42 degrees C, at doses that did not cause robust thermal antinociceptive effects. At the largest doses studied, ketamine but not MK-801 also briefly reversed ongoing capsaicin-induced allodynia. The present model of topical capsaicin administration may be used to study antiallodynic effects of opioid and nonopioid compounds, as well as their ability to prevent and reverse allodynia, in unanesthetized nonhuman primates in the absence of tissue disruption.

66A-078:a kappa-opiate receptor agonist for amelioration of spinal spasticity.

The effect and mechanism of kappa opiate receptor agonist and high-frequency electrostimulation of acupoints in treating spinal spasticity were studied. The spinal spastic models were made by gradual mechanical compression on the cervical spinal cord of rabbits. 24 prepared rabbits were divided into 3 groups randomly, and each group with 8 rabbits was given intrathecally kappa-receptor agonist 66A-078, kappa-receptor antagonist +66A-078 and normal saline respectively. The degree of spasticity was quantified by both clinical score and electrophysiological examinations. The result showed that the spasticity was markedly inhibited by intrathecal injection of 66A-078 and that the kappa-receptor antagonist (naloxone) reversed this effect. We can infer that the antispastic effect of 66A-078 is mediated by kappa-receptors. This result is helpful in explaining the immediate antispastic mechanism of high-frequency electrostimulation of acupoints discussed in previous study.

Evaluation on the treatment of morphine addiction by acupuncture Chinese herbs and opioid peptides.

Experimental studies on the effects of acupuncture, combined Chinese herbs, and opioid peptides on morphine withdrawal symptoms were carried out in 119 addicted rats. Electroacupuncture was found to be the most effective method as it reduced the morphine withdrawal scores to -85%. The combined herbs, Qiang Huo, Gou Teng, Chuan Xion, Fu Zi and Yan Hu Suo suppressed the withdrawal scores of -68%. The opioid peptides, endorphin, enkephalin, and dynorphin, produced marked sedative effect and alleviated the withdrawal symptoms, reducing the scores from -28% to -74%. It is suggested that acupuncture and herbs, being non-opiate and having less side effect, might be used as alternative or supplementary treatment on morphine addiction.

[Protective action of endogenous opioid-like peptides of different origins in duodenal ulcer in rats]. / Zashchitnoe deistvie éndogennykh opiopodobnykh peptidov razlichnogo proiskhozhdeniia pri duodenal'noi iazve u krys.

A study was made of the effects of some endogenous opioids (beta-endorphin, gamma-endorphin, met-enkephalin, leu-enkephalin and dinorphin) formed in the body from different high-molecular precursors (pro-opiomelanocortin, proenkephalins A and B) on the development in rats of the cysteamine-induced duodenal ulcers. All the peptides under study, gamma-endorphin, in particular, had an anti-ulcerous activity which was mediated by specific opiate receptors. The majority of the opioids was characterized by reduction of the anti-ulcerous effect as the dose was raised. It is assumed that protection of the duodenal mucosa under ulcerogenic exposures is an essential property of endogenous peptides. It is concluded that opioid peptides derived from different precursors are arranged in a complex synergic system responsible for cytoprotection of the duodenum.