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Subcellular targeting and packaging of opioids and receptors Robert P. Elde, Ph.D. Professor of Neuroscience & Dean, College of Biological Sciences

Dr. Elde's research is focused primarily on the trafficking of opioid receptors and their endogenous peptides. Shortly after the three opioid receptor subtypes (mu, delta, and kappa) were cloned, he raised antisera to these receptors and mapped their distribution in the mammalian nervous systems. In the process, it was discovered that some opioid receptors, primarily the delta receptor but in some regions the mu or the kappa receptor as well, were localized in axonal processes. This localization on presynaptic nerve terminals permits modulation of neuropeptide activity at the site of release, thus allowing local inhibition of neuropeptide release. Furthermore, it was discovered that the majority of presynaptic opioid receptor immunoreactivity was not found associated with the plasma membrane of nerve terminals, but was instead found associated with large vesicles within the nerve terminal. Work in the neural lobe of the pituitary revealed that stimulation causes these receptors to be translocated from neuropeptide-containing vesicles in the axon terminal and inserted into the plasma membrane during the fusion event that causes neuropeptide release.

In addition to Dr. Elde's work in the study of the cell biology of opioid receptors and ligands that ameliorate pain, he has done extensive work in the localization of various ion channels involved in the transmission of painful stimuli. Since the first order neuron in the pain pathway is the primary afferent neuron, these studies focused on the distribution of these ion channels in dorsal root ganglion (DRG) neurons. He found that the ATP-gated ion channel P2X3 is localized primarily on non-peptide containing neurons while the heat-gated capsaicin sensitive receptor VR-1 is localized on both peptide and non-peptide containing DRG neurons and the acid sensing ion channels, the ASICS, are localized primarily on peptide containing DRG neurons.

Confocal micrograph of rat dorsal root ganglion neurons showing the ATP-gated ion channel P2X3 immunoreactivity in red, the lectin IB4 staining in green, and the neuropeptide substance P immunoreactivity in blue.

More recently, at least 15 additional splice variants (MOR1A-P) and two endogenous ligands (endomorphin 1 and endomorphin 2) of the mu opioid receptor have been identified. These receptors and ligands have been identified in primary afferent neurons, but their distribution within subsets of dorsal root ganglion neurons and their subcellular localization is unknown. Some of the ongoing work in the laboratory studies the distribution of these receptors and ligands in primary afferent neurons at both the confocal microscopic and electron microscopic level.

Selected Publications

Guo A, Simone DA, Stone LS, Fairbanks CA, Wang J, Elde R. 2001. Developmental shift of vanilloid receptor 1 (VR1) terminals into deeper regions of the superficial dorsal horn: correlation with a shift from TrkA to Ret expression by dorsal root ganglion neurons. Eur J Neurosci 14: 293-304.

Guo A, Vulchanova L, Wang J, Li X, Elde R. 1999. Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur J Neurosci 11: 946-58.

Hauser KF, Houdi AA, Turbek CS, Elde RP, Maxson W, 3rd. 2000. Opioids intrinsically inhibit the genesis of mouse cerebellar granule neuron precursors in vitro: differential impact of mu and delta receptor activation on proliferation and neurite elongation. Eur J Neurosci 12: 1281-93.

Hellstrom J, Arvidsson U, Elde R, Cullheim S, Meister B. 1999. Differential expression of nerve terminal protein isoforms in VAChT-containing varicosities of the spinal cord ventral horn. J Comp Neurol 411: 578-90.

Kang T, Yi J, Guo A, Wang X, Overall CM, Jiang W, et al. 2001. Subcellular distribution and cytokine- and chemokine-regulated secretion of leukolysin/MT6-MMP/MMP-25 in neutrophils. J Biol Chem 276: 21960-8.

Ko JL, Arvidsson U, Williams FG, Law PY, Elde R, Loh HH. 1999. Visualization of time-dependent redistribution of delta-opioid receptors in neuronal cells during prolonged agonist exposure. Brain Res Mol Brain Res 69: 171-85.

Mezey E, Toth ZE, Cortright DN, Arzubi MK, Krause JE, Elde R, et al. 2000. Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc Natl Acad Sci U S A 97: 3655-60.

O'Donnell AM, Ellis LM, Riedl MS, Elde RP, Mawe GM. 2001. Distribution and chemical coding of orphanin FQ/nociceptin-immunoreactive neurons in the myenteric plexus of guinea pig intestines and sphincter of Oddi. J Comp Neurol 430: 1-11.

Pare M, Elde R, Mazurkiewicz JE, Smith AM, Rice FL. 2001. The Meissner corpuscle revised: a multiafferented mechanoreceptor with nociceptor immunochemical properties. J Neurosci 21: 7236-46.

Robertson B, Schulte G, Elde R, Grant G. 1999. Effects of sciatic nerve injuries on delta -opioid receptor and substance P immunoreactivities in the superficial dorsal horn of the rat. Eur J Pain 3: 115-129.

Shuster SJ, Riedl M, Li X, Vulchanova L, Elde R. 1999. Stimulus-dependent translocation of kappa opioid receptors to the plasma membrane. J Neurosci 19: 2658-64.

Shuster SJ, Riedl M, Li X, Vulchanova L, Elde R. 2000. The kappa opioid receptor and dynorphin co-localize in vasopressin magnocellular neurosecretory neurons in guinea-pig hypothalamus. Neuroscience 96: 373-83.

Stone LS, Vulchanova L, Riedl MS, Wang J, Williams FG, Wilcox GL, et al. 1999. Effects of peripheral nerve injury on alpha-2A and alpha-2C adrenergic receptor immunoreactivity in the rat spinal cord. Neuroscience 93: 1399-407.

Vulchanova L, Olson TH, Stone LS, Riedl MS, Elde R, Honda CN. 2001. Cytotoxic targeting of isolectin IB4-binding sensory neurons. Neuroscience 108: 143-55.

Yu W, Hao JX, Xu XJ, Hokfelt T, Elde R, Wiesenfeld-Hallin Z. 1999. Spinal cord ischemia reduces mu-opioid receptors in rats: correlation with morphine insensitivity. Neuroreport 10: 87-91.

Zhang X, de Araujo Lucas G, Elde R, Wiesenfeld-Hallin Z, Hokfelt T. 2000. Effect of morphine on cholecystokinin and mu-opioid receptor-like immunoreactivities in rat spinal dorsal horn neurons after peripheral axotomy and inflammation. Neuroscience 95: 197-207.

Zhu Y, King MA, Schuller AG, Nitsche JF, Reidl M, Elde RP, et al. 1999. Retention of supraspinal delta-like analgesia and loss of morphine tolerance in delta opioid receptor knockout mice. Neuron 24: 243-52.