This proposal is concerned with the effects of opioid peptides on the calcium metabolism of dorsal root ganglion (DRG) sensory neurons. Opioid peptides are a class of neurotransmitter and hormone that bind at the same sites in the nervous system as opiates, which act through mimicry of the endogenous opioid peptides. DRG neurons are responsible for transducing all the sensations we feel below the head and transmitting the sensory signal into the spinal cord by means of a calcium-evoked release of neurotransmitter. The inhibition of this secretory event is the essence of opioid and opiate action at this first step in the pathway of sensation. The long-term goal of this work is a full description of the cellular basis of this inhibition. We intend to concentrate on the mu-type opioid receptor, the primary binding site for morphine. Our preliminary results show, surprisingly, that certain types of calcium channels are inhibited by activation of the mu receptor. The biochemical link between the mu receptor and these Ca channels will be pursued using the patch clamp technique in combination with intracellular application, either by dialysis or flash photolysis, of proteins and 2nd messengers that might be involved in receptor- effector coupling. A second major aim is to observe the effect of opioids on intracellular calcium transients measured with the fluorescent calcium indicator, fura-2. The particular concern is whether opioids affect cytoplasmic calcium uptake or intracellular calcium release in addition to their effects on surface membrane calcium entry. The fura system will also allow us to measure the effect on intracellular calcium of the inhibition of Ca channels that we have observed. Finally, the heterogeneity of the response to mu opioids among different sensory neurons will be pursued. Is this heterogeneity a reflection of selective opioid action on cells encoding particular sensations? Labelling techniques allow us to determine the spinal lamina at which a neuron projects and the tissue that the neuron innervates. Do particular neuronal subsets show distinct opioid sensitivity, or lack thereof?

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National Institute on Drug Abuse (NIDA)
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Drug Abuse Biomedical Research Review Committee (DABR)
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Washington University
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Saint Louis
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Benson, C J; Sutherland, S P (2001) Toward an understanding of the molecules that sense myocardial ischemia. Ann N Y Acad Sci 940:96-109
Benson, C J; Eckert, S P; McCleskey, E W (1999) Acid-evoked currents in cardiac sensory neurons: A possible mediator of myocardial ischemic sensation. Circ Res 84:921-8
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Womack, M D; McCleskey, E W (1995) Interaction of opioids and membrane potential to modulate Ca2+ channels in rat dorsal root ganglion neurons. J Neurophysiol 73:1793-8
Nah, S Y; McCleskey, E W (1994) Ginseng root extract inhibits calcium channels in rat sensory neurons through a similar path, but different receptor, as mu-type opioids. J Ethnopharmacol 42:45-51
McCleskey, E W (1994) Calcium channels: cellular roles and molecular mechanisms. Curr Opin Neurobiol 4:304-12
Fieber, L A; McCleskey, E W (1993) L-type calcium channels in type I cells of the rat carotid body. J Neurophysiol 70:1378-84

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