Opioid Receptor Trafficking in Pain States

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1 Encyclopedia of Pain Springer-Verlag Berlin Heidelberg / _2962 Robert F. Schmidt and William D. Willis Opioid Receptor Trafficking in Pain States Catherine M. Cahill 3, Anne Morinville 4 and Alain Beaudet 4 (3) Queen s University, Kingston, ON, Canada (4) Montreal Neurological Institute, McGill University, Montreal, QC, Canada Catherine M. Cahill cahillc@post.queensu.ca Anne Morinville annemorinville@yahoo.ca Alain Beaudet abeaudet@frsq.gouv.gc.ca Without Abstract Synonyms Trafficking; opioid receptor targeting; opioid receptor recruitment; opioid receptor sorting; opioid receptor redistribution Definition Receptor trafficking is the constitutive or regulated movement of a receptor protein within the cell, whether between sub-cellular compartments, or towards or away from plasma membranes. The presence of opioid receptors (OR) at the cell surface is essential for regulating opioid signal transduction and subsequent cellular functions. Following agonist activation, receptor internalization plays an important role in cellular responsiveness, by depleting the cell surface of receptors and contributing to the processes of receptor desensitization and re-sensitization. Likewise, receptor insertion in plasma membranes through recycling of internalized receptors, and/or targeting of reserve receptors from intracellular stores, is critical for controlling the number of plasma membrane receptors accessible for stimulation, and thereby for regulating various neuronal responses including pain transmission. 1 of :39 PM

2 Characteristics Background Three genes have been identified to encode for three opioid receptors (OR): mu (μ), delta (δ), and kappa (κ). All OR inhibit the transmission of pain and are located on peripheral and central branches of somatic and visceral sensory afferents, as well as at various locations within the central nervous system including the spinal cord, midbrain, and cerebral cortex. Within the last few decades, great advances have been made in our understanding of the physiological and pharmacological properties of OR, as well as of their implication in mechanisms of acute and chronic pain. By comparison, much less is known about the mechanisms of OR intraneuronal trafficking, specifically, the physiological function or maladaptive processes that are linked to these trafficking events (for reviews see Roth et al. 1998; von Zastrow et al. 2003). The first documentation of OR trafficking in models of persistent and chronic pain was generated by studies on axonal transport in peripheral sensory afferents. Thus, autoradiographic and immunohistochemical studies have demonstrated that induction of inflammatory pain via local injection of chemical irritants, antigens, or cytokines resulted in an increase in the synthesis and expression of OR in the cell bodies of sensory afferent neurons (dorsal root ganglia, DRG). This increased expression led, in turn, to enhanced axonal transport of OR in the sciatic nerve, and hence to an increase in their density in the inflamed tissue (Hassan et al. 1993; Ji et al. 1995). Ligation of the nerve following induction of tissue inflammation resulted in an accumulation of all three OR in the sciatic nerve, both proximal and distal to site of ligation, indicating both antero- and retrograde transport of multiple OR. This enhanced transport was postulated to underlie the augmented antinociceptive potency of OR agonists following either spinal or local administration of opiates in models of inflammation (Antonijevic et al. 1995; Cahill et al. 2003). Similarly, μor were found to be up-regulated in DRG ipsilateral to the site of nerve injury in a model of neuropathic pain (Truong et al. 2003). In this latter study, the OR protein was trafficked to axonal endbulbs of Cajal just proximal to the site of nerve injury, within aberrantly regenerating small axons in the epineurial sheath, and in residual small axons distal to the nerve constriction. These changes resulted in an increase in anti-allodynic and anti-hyperalgesic effects of locally or peripherally applied opioid agonists, suggesting that the accumulation of μor to sites of neuromas, and concomitant disruption of the blood nerve barrier, provided a means for enhanced agonist access to the receptors (Antonijevic et al. 1995). Cell Trafficking of δor in Chronic Pain We postulated that, likewise, changes in receptor trafficking might underlie the enhanced antinociceptive potency of δor agonists administered intrathecally in rodents with unilateral hind paw inflammation (Hylden et al. 1991; Qiu et al. 2000). To test this hypothesis, we used electron microscopic immunocytochemistry to quantify the ultrastructural distribution of δor in neurons of the dorsal spinal cord of rats and mice, subjected, or not, to peripheral inflammation via intraplantar injection of Complete Freundʼs Adjuvant (CFA). In non-treated animals, the bulk of δor immunoreactivity was associated with neuronal cell bodies and dendrites, in conformity with in situ hybridization and radioligand binding data (Cahill et al. 2001a). Within these structures, only a small proportion of immunoreactive receptors were found on the plasma membrane, the majority being associated with intracellular vesicular stores (Cahill et al. 2001a; Cheng et al. 1997). By contrast, 72h after CFA injection, the proportion of δor associated with plasma membranes was 2 of :39 PM

significantly increased in both species within dendrites from laminae III V of the dorsal horn ipsilateral to the side of inflammation, compared to both untreated controls and to the contralateral

3 significantly increased in both species within dendrites from laminae III V of the dorsal horn ipsilateral to the side of inflammation, compared to both untreated controls and to the contralateral spinal cord (Cahill et al. 2003; Morinville et al. 2004a). This change in sub-cellular compartmentalization was positively correlated with an augmented antinociceptive effect of δor agonists following spinal administration (Cahill et al. 2003). The increase in δor plasma membrane density was partly due to recruitment of reserve receptors from intracellular reserve stores, since it was accompanied by a statistical decrease in the mean distance separating intracellular receptors from the closest plasma membrane. Figure 1 Trafficking of δor to neuronal plasma membranes of postsynaptic neurons in the dorsal spinal cord following induction of peripheral inflammation. Electron microscopic distribution of δor in dendrites from the ipsilateral dorsal spinal cord of sham-injected (a) versus CFA-injected (b) rats. Silver-intensified immunogold labeling of δor demonstrates a predominantly intracellular localization of the receptor in both conditions. However, the number of gold particles is higher over the plasma membrane of dendrites in CFA-treated than in sham-injected animals (arrows). (c) Quantitative analysis of the subcellular distribution of immunoreactive δor in dendrites from the lumbar spinal cord of untreated wild-type (WT), CFA-treated WT, and µor knock-out (KO) mice. Data are expressed as the percentage of dendrite-associated gold particles present on plasma membranes. Note that the percentage of membrane-associated δor is significantly higher in CFA-injected than in sham-treated WT mice, and that this effect is absent in CFA-treated µor KO mice. D, dendrite; At, axon terminal. Scale bar = 0.4 µm. A similar increase in the targeting of δor to neuronal plasma membranes had previously been documented by us in rats and mice subjected to sustained treatment with morphine for 48h (Cahill et al. 2001b; Morinville et al. 2003). Similar to the results obtained in CFA-treated mice, this increase in δor targeting was not accompanied by corresponding augmentations in either δor mrna, protein expression, or [ 125 I] deltorphin binding levels, suggesting that it was not due to enhanced receptor production, but solely to increased recruitment to the surface (Morinville et al. 2004b). Most importantly, this targeting effect of morphine was the result of a selective stimulation of μor, as it was no longer observed in μor-ko mice (Morinville et al. 2003). To determine whether the CFA-induced targeting of δor to dendritic membranes was also due to stimulation of μor, we repeated the CFA experiments in transgenic μor knock-out animals. The CFA-induced recruitment of δor to neuronal plasma membranes was totally abolished in these animals, suggesting that it was dependent on the activation of μor through pain-induced release of endogenous μor-acting peptides (Morinville et al. 2004a). Functional Significance In summary, alterations in the sub-cellular distribution of OR, as the result of either acute or chronic 3 of :39 PM

4 stimulation, or of adaptive changes in response to injury, can have dramatic pathophysiological consequences on pain transmission. In the case of δor, the increase in cell surface receptor density induced by the chronic inflammatory pain process has major pharmacological implications in allowing for increased therapeutic efficacy of analgesic drugs selective for the δor. In other pain model systems, OR have been demonstrated to be involved in activity-dependent synaptic plasticity, a process known to be fundamental to the development of chronic pain states (Woolf & Salter 2000). Studying phenomena of receptor trafficking and internalization will hopefully provide another venue that allows either better diagnostic, or alternative novel, strategies for the treatment of chronic pain syndromes. References 1. Antonijevic I, Mousa SA, Schafer M., Stein C (1995) Perineurial Defect and Peripheral Opioid Analgesia in Inflammation. J Neurosci 15: Cahill CM, McClellan KA, Morinville A, Hoffert C, Hubatsch D, O Donnell D, Beaudet A (2001a) Immunocytochemical Distribution of delta Opioid Receptors in Rat Brain: Antigen-Specific Sub-Cellular Compartmentalization. J CompNeurol 440: Cahill CM, Morinville A, Hoffert C, Hubatsch D, O Donnell D, Beaudet A (2003) Up-Regulation and Trafficking of δor in a Model of Chronic Inflammatory Pain; Positive Correlation with Enhanced D-[Ala2]deltorphin-Induced Antinociception. Pain 101: Cahill CM, Morinville A, Lee M-C, Vincent JP, Beaudet A (2001b) Targeting of delta Opioid Receptor to the Plasma Membrane following Chronic Morphine Treatment. J Neurosci 21: Cheng PY, Liu-Chen LY, Pickel VM (1997) Dual Ultrastructural Immunocytochemical Labeling of mu and delta Opioid Receptors in the Superficial Layers of the Rat Cervical Spinal Cord. Brain Res 778: Hassan AH, Ableitner A, Stein C, Herz A (1993) Inflammation of the Rat Paw Enhances Axonal Transport of Opioid Receptors in the Sciatic Nerve and Increases their Density in the Inflamed Tissue. Neuroscience 55: Hylden JL, Thomas DA, Iadarola MJ, Nahin RL, Dubner R (1991). Spinal Opioid Analgesic Effects are Enhanced in a Model of Unilateral Inflammation/Hyperalgesia: Possible Involvement of Noradrenergic Mechanisms. Eur J Pharmacol 194: Ji RR, Zhang Q, Law PY, Loh HH, Elde R, Hökfelt T (1995) Expression of mu-, delta-, and kappa-opioid Receptor-Like Immunoreactivities in Rat Dorsal Root Ganglia after Carrageenan-Induced Inflammation. J Neurosci 15: Morinville A, Cahill CM, Esdaile MJ, Aibak H, Collier B, Kieffer BL, Beaudet A (2003) Regulation of delta Opioid Receptor Trafficking through mu-opioid Receptor Stimulation: Evidence from mu-opioid Receptor Knock-Out Mice. J Neurosci 23: of :39 PM

5 10. Morinville A, Cahill CM, Kieffer B, Collier B, Beaudet A (2004) Mu Opioid Receptor Knockout Prevents Changes in delta-opioid Receptor Trafficking Induced by Chronic Inflammatory Pain. Pain 109: Morinville A, Cahill CM, Aibak H et al. (2004b) Morphine-induced changes in delta opioid receptor trafficking are linked to somatosensory processing in the rat spinal cord. J Neurosci 24: Qiu C, Sora I, Ren K, Uhl G, Dubner R (2000) Enhanced delta-opioid Receptor-Mediated Antinociception in mu-opioid Receptor-Deficient Mice. Eur J Pharmacol 387: Roth BL, Willins DL, Kroeze WK (1998) G Protein-Coupled Receptor (GPCR) Trafficking in the Central Nervous System: Relevance for Drugs of Abuse. Drug Alcohol Depend 51: Truong W, Cheng C, Xu QG, Li XQ, Zochodne DW (2003) Mu Opioid Receptors and Analgesia at the Site of a Peripheral Nerve Injury. Ann Neurol 53: von Zastrow M, Svingos A, Haberstock-Debic H, Evans C (2003) Regulated Endocytosis of Opioid Receptors: Cellular Mechanisms and Proposed Roles in Physiological Adaptation to Opiate Drugs. Curr Opin Neurobiol 13: Woolf, C.J., Salter, M.W. (2000). Neuronal Plasticity: Increasing the Gain in Pain. Science 288: of :39 PM

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