Transgenic Mouse Model for Screening Analgesic Agents
Background: UC Case No.: 2004-692 Patent Application Publication No.: WO/2006/017293 International Application No.: PCT/US2005/024697
This invention is an animal model and various cell-based models to determine nociception, pain transduction, and pain threshold.
Researchers at the University of California, Irvine, discovered that overexpression of voltage-gated calcium channel alpha-2-delta-l subunit in neural tissue, and especially increased expression in spinal cord and dorsal root ganglia in transgenic mice, correlates in vivo with typical nerve injury-induced nociceptive responses to innocuous mechanical and thermal stimulation (tactile allodynia and thermal hyperalgesia).
Significantly, such transgenic animals can be used to investigate nerve injury-induced neuropathic pain without inflicting nerve injury to the animals, which often interferes with test results.
Similarly, neural cells obtained from such transgenic animals or neural cells transformed by overexpressing the alpha-2-delta-l subunit exhibit physiological parameters remarkably similar to those of neural tissue obtained from animals thought to have nerve injury-induced neuropathic pain.
Technology: A model for peripheral nerve injury-induced neuropathic pain in an animal expresses the alpha-2-delta-l subunit of a voltage gated calcium channel in neuronal tissue in an amount sufficient to produce non-injurious tactile allodynia and/or thermal hyperalgesia, while retaining normal pain reaction to inflammatory pain (as compared to a control animal). Typically, the alpha-2-delta-l subunit is expressed in the hippocampus, the cortex, the spinal cord, and the dorsal root ganglion, and is substantially not expressed in the heart, skeletal muscles, the lung, kidneys, the spleen, and/or the intestines. The expression is facilitated using various molecular biology and genetic techniques. Application: The prepared transgenic mice overexpressing the calcium channel alpha- 2-delta-l subunit in neurons have hypersensitivity to mechanical and thermal stimuli, mimicking pain states after injuries such as nerve injuries, neuropathies and inflammation involving neural tissue.
Methods of testing a pharmaceutically active compound for use in treatment of peripheral nerve injury-induced neuropathic pain, including a step in which the compounds are administered in vivo to the transgenic animal (or recombinant cell, which may or may not be isolated from the transgenic animal). Suitable compounds for reduction of neuropathic pain include those that reduce expression and/or activity of the alpha-2-delta-l subunit or a component that is functionally associated with the alpha-2-delta-l subunit.
This transgenic mouse allows determination of the metabolic effects of a drug in vivo (e.g., the animal metabolizes the compound to generate an active metabolite that is effective to reduce the allodynia and/or hyperalgesia).
Consequently, this injury- free transgenic mouse model provides an excellent tool for screening compounds related to the development and evaluation of pain medications (e.g., inhibitors of the alpha-2-delta-l subunit that act as modulating agents, reduce expression of the alpha-2-delta-l subunit or functionally associated component, and/or reduce pain perception of an individual), and for mechanistic studies of pain transduction mechanisms.
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