Mechanism of allodynia evoked by intrathecal morphine-3-glucuronide in mice.

Morphine-3-glucuronide (M3G), a main metabolite of morphine, has been proposed as a responsible factor when patients present with the neuroexcitatory side effects (allodynia, hyperalgesia, and myoclonus) observed following systemic administration of large doses of morphine. Indeed, both high-dose morphine (60 nmol/5 microl) and M3G (3 nmol/5 microl) elicit allodynia when administered intrathecally (i.t.) into mice. The allodynic behaviors are not opioid receptor mediated. This chapter reviews the potential mechanism of spinally mediated allodynia evoked by i.t. injection of M3G in mice. We discuss a possible presynaptic release of nociceptive neurotransmitters/neuromodulators such as substance P, glutamate, and dynorphin in the primary afferent fibers following i.t. M3G. It is possible to speculate that i.t. M3G injection could activate indirectly both NK(1) receptor and glutamate receptors that lead to the release of nitric oxide (NO) in the dorsal spinal cord. The NO plays an important role in M3G-induced allodynia. The phosphorylation of extracellular signal-regulated protein kinase (ERK) in the dorsal spinal cord evoked via NO/cGMP/PKG pathway contributes to i.t. M3G-induced allodynia. Furthermore, the increased release of NO observed after i.t. injection of M3G activates astrocytes and induces the release of the proinflammatory cytokine, interleukin-1beta. Taken together, these findings suggest that M3G may induce allodynia via activation of NO-ERK pathway, while maintenance of the allodynic response may be triggered by NO-activated astrocytes in the dorsal spinal cord. The demonstration of the cellular mechanisms of neuronal-glial interaction underlying M3G-induced allodynia provides a fruitful strategy for improved pain management with high doses of morphine.

A unique therapeutic approach to emesis and itch with a proanthocyanidin-rich genonutrient.

BACKGROUND: We examined the therapeutic potential of a proprietary Croton palanostigma extract (Zangrado(R)) in the management of emesis and itch. METHODS: Emesis was induced in ferrets with morphine-6-glucuronide (0.05 mg/kg sc) in the presence of Zangrado (3 mg/kg, ip) and the cannabinoid receptor 1 antagonist, AM 251 (5 mg/kg, ip). Topical Zangrado (1%) was assessed for anti-pruretic actions in the 5-HT-induced scratching model in rats and evaluated in capsaicin-induced gastric hyperemia as measured by laser doppler flow. In the ApcMinmouse model of precancerous adenomatosis polyposis, mice received Zangrado (100 mug/ml in drinking water) from the age of 6 - 16 weeks for effects on polyp number. In RAW 264.7 cells Zangrado was examined for effects on lipopolysaccharide-induced nitrite production. RESULTS: Zangrado was a highly effective anti-emetic, reducing morphine-induced vomiting and retching by 77%. These benefits were not associated with sedation or hypothermia and were not reversed by cannabinoid receptor antagonism. Itch responses were blocked in both the morphine and 5-HT models. Zangrado did not exacerbate the ApcMincondition rather health was improved. Capsaicin-induced hyperemia was blocked by Zangrado, which also attenuated the production of nitric oxide by activated macrophages. CONCLUSION: Zangrado is an effective anti-emetic and anti-itch therapy that is devoid of common side-effects, cannabinoid-independent and broadly suppresses sensory afferent nerve activation. This complementary medicine represents a promising new approach to the management of nausea, itch and irritable bowel syndrome.