Molecular and cellular mechanisms of the age-dependency of opioid analgesia and tolerance

Molecular Pain

Yu-guang Huang²  Pamela Pierce Palmer³  Guo-xi Xie³  Xin Xin¹  Jing Zhao¹ 

[1] Department of Anesthesia, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China;Department of Anesthesia, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, No.1 Shuaifuyuan Str., Wangfujing Ave., Dongcheng District, Beijing, 100730, China;Department of Anesthesiology and Perioperative Care, University of California, San Francisco, CA, 94143, USA

关键词: Opioid tolerance;    Age-dependency;    Molecular and cellular mechanisms;   

Others  :  863847
DOI  :  10.1186/1744-8069-8-38

 received in 2011-11-30, accepted in 2012-05-09,  发布年份 2012

【 摘 要 】

The age-dependency of opioid analgesia and tolerance has been noticed in both clinical observation and laboratory studies. Evidence shows that many molecular and cellular events that play essential roles in opioid analgesia and tolerance are actually age-dependent. For example, the expression and functions of endogenous opioid peptides, multiple types of opioid receptors, G protein subunits that couple to opioid receptors, and regulators of G protein signaling (RGS proteins) change with development and age. Other signaling systems that are critical to opioid tolerance development, such as N-methyl-D-aspartic acid (NMDA) receptors, also undergo age-related changes. It is plausible that the age-dependent expression and functions of molecules within and related to the opioid signaling pathways, as well as age-dependent cellular activity such as agonist-induced opioid receptor internalization and desensitization, eventually lead to significant age-dependent changes in opioid analgesia and tolerance development.

【 授权许可】

   
2012 Zhao et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Vigano A, Bruera E, Suarez-Almazor ME: Age, pain intensity, and opioid dose in patients with advanced cancer. Cancer 1998, 83:1244-1250.
• [2]Hall S, Gallagher RM, Gracely E, Knowlton C, Wescules D: The terminal cancer patient: effects of age, gender, and primary tumor site on opioid dose. Pain Med 2003, 4:125-134.
• [3]Clark JD: Chronic pain prevalence and analgesic prescribing in a general medical population. J Pain Symptom Manage 2002, 23:131-137.
• [4]Savage SR: Opioid therapy of chronic pain: assessment of consequences. Acta Anaesthesiol Scand 1999, 43:909-917.
• [5]Paice JA, Penn RD, Shott S: Intraspinal morphine for chronic pain: a retrospective, multicenter study. J Pain Symptom Manage 1996, 11:71-80.
• [6]Mystakidou K, Parpa E, Tsilika E, Mavromati A, Smyrniotis V, Georgaki S, Vlahos L: Long-term management of noncancer pain with transdermal therapeutic system-fentanyl. J Pain 2003, 4:298-306.
• [7]Robinson RC, Gatchel RJ, Polatin P, Deschner M, Noe C, Gajraj N: Screening for problematic prescription opioid use. Clin J Pain 2001, 17:220-228.
• [8]Buntin-Mushock C, Phillip L, Moriyama K, Palmer PP: Age-dependent opioid escalation in chronic pain patients. Anesth Analg 2005, 100:1740-1745.
• [9]Moulin DE, Iezzi A, Amireh R, Sharpe WK, Boyd D, Merskey H: Randomised trial of oral morphine for chronic non-cancer pain. Lancet 1996, 347:143-147.
• [10]Jourdan D, Pickering G, Marchand F, Gaulier JM, Alliot J, Eschalier A: Impact of ageing on the antinociceptive effect of reference analgesics in the Lou/c rat. Br J Pharmacol 2002, 137:813-820.
• [11]O'Callaghan JP, Holtzman SG: Prenatal administration of morphine to the rat: tolerance to the analgesic effect of morphine in the offspring. J Pharmacol Exp Ther 1976, 197:533-544.
• [12]Windh RT, Little PJ, Kuhn CM: The ontogeny of mu opiate tolerance and dependence in the rat: antinociceptive and biochemical studies. J Pharmacol Exp Ther 1995, 273:1361-1374.
• [13]Zhu H, Barr GA: Ontogeny of NMDA receptor-mediated morphine tolerance in the postnatal rat. Pain 2003, 104:437-447.
• [14]Nozaki M, Akera T, Lee CY, Brody TM: The effects of age on the development of tolerance to and physical dependence on morphine in rats. J Pharmacol Exp Ther 1975, 192:506-512.
• [15]Wang Y, Mitchell J, Moriyama K, Kim KJ, Sharma M, Xie GX, Palmer PP: Age-dependent morphine tolerance development in the rat. Anesth Analg 2005, 100:1733-1739.
• [16]Van Praag H, Frenk H: Evidence for opiate tolerance in newborn rats. Brain Res Dev Brain Res 1991, 60:99-102.
• [17]Thornton SR, Wang AF, Smith FL: Characterization of neonatal rat morphine tolerance and dependence. Eur J Pharmacol 1997, 340:161-167.
• [18]Trujillo KA, Akil H: Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 1991, 251:85-87.
• [19]Fan GH, Wang LZ, Qiu HC, Ma L, Pei G: Inhibition of calcium/calmodulin-dependent protein kinase II in rat hippocampus attenuates morphine tolerance and dependence. Mol Pharmacol 1999, 56:39-45.
• [20]Fanselow MS, Cramer CP: The ontogeny of opiate tolerance and withdrawal in infant rats. Pharmacol Biochem Behav 1988, 31:431-438.
• [21]Laferriere A, Colin-Durand J, Moss IR: Ontogeny of respiratory sensitivity and tolerance to the mu-opioid agonist fentanyl in rat. Brain Res Dev Brain Res 2005, 156:210-217.
• [22]Thornton SR, Smith FL: Characterization of neonatal rat fentanyl tolerance and dependence. J Pharmacol Exp Ther 1997, 281:514-521.
• [23]Zissen MH, Zhang G, McKelvy A, Propst JT, Kendig JJ, Sweitzer SM: Tolerance, opioid-induced allodynia and withdrawal associated allodynia in infant and young rats. Neuroscience 2007, 144:247-262.
• [24]Ma W, Zheng WH, Kar S, Quirion R: Morphine treatment induced calcitonin gene-related peptide and substance P increases in cultured dorsal root ganglion neurons. Neuroscience 2000, 99:529-539.
• [25]Przewlocki R: Opioid abuse and brain gene expression. Eur J Pharmacol 2004, 500:331-349.
• [26]Ammon-Treiber S, Hollt V: Morphine-induced changes of gene expression in the brain. Addict Biol 2005, 10:81-89.
• [27]Bagley EE, Chieng BC, Christie MJ, Connor M: Opioid tolerance in periaqueductal gray neurons isolated from mice chronically treated with morphine. Br J Pharmacol 2005, 146:68-76.
• [28]Przewlocki R, Przewlocka B: Opioids in neuropathic pain. Curr Pharm Des 2005, 11:3013-3025.
• [29]Hepler JR: Emerging roles for RGS proteins in cell signalling. Trends Pharmacol Sci 1999, 20:376-382.
• [30]Wang D, Sun X, Bohn LM, Sadee W: Opioid receptor homo- and heterodimerization in living cells by quantitative bioluminescence resonance energy transfer. Mol Pharmacol 2005, 67:2173-2184.
• [31]Lutfy K, Hossain SM, Khaliq I, Maidment NT: Orphanin FQ/nociceptin attenuates the development of morphine tolerance in rats. Br J Pharmacol 2001, 134:529-534.
• [32]De Vries TJ, Jonker AJ, Voorn P, Mulder AH, Schoffelmeer AN: Adaptive changes in rat striatal preproenkephalin expression and dopamine-opioid interactions upon chronic haloperidol treatment during different developmental stages. Brain Res Dev Brain Res 1994, 78:175-181.
• [33]Tseng LF, Collins KA, Wang Q: Differential ontogenesis of thermal and mechanical antinociception induced by morphine and beta-endorphin. Eur J Pharmacol 1995, 277:71-76.
• [34]Volterra A, Brunello N, Restani P, Galli CL, Racagni G: Ontogenetic studies on mu, delta and kappa opioid receptors in rat brain. Pharmacol Res Commun 1986, 18:979-990.
• [35]Hoskins DL, Gordon TL, Crisp T: The effects of aging on mu and delta opioid receptors in the spinal cord of Fischer-344 rats. Brain Res 1998, 791:299-302.
• [36]Rahman W, Dashwood MR, Fitzgerald M, Aynsley-Green A, Dickenson AH: Postnatal development of multiple opioid receptors in the spinal cord and development of spinal morphine analgesia. Brain Res Dev Brain Res 1998, 108:239-254.
• [37]Zhang AZ, Pasternak GW: Ontogeny of opioid pharmacology and receptors: high and low affinity site differences. Eur J Pharmacol 1981, 73:29-40.
• [38]Hoskins B, Ho IK: Age-induced differentiation of morphine's effect on cyclic nucleotide metabolism. Neurobiol Aging 1987, 8:473-476.
• [39]Bardo MT, Bhatnagar RK, Gebhart GF: Differential effects of chronic morphine and naloxone on opiate receptors, monoamines, and morphine-induced behaviors in preweanling rats. Brain Res 1982, 256:139-147.
• [40]Pitcher JA, Freedman NJ, Lefkowitz RJ: G protein-coupled receptor kinases. Annu Rev Biochem 1998, 67:653-692.
• [41]Ferguson SS, Barak LS, Zhang J, Caron MG: G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins. Can J Physiol Pharmacol 1996, 74:1095-1110.
• [42]Luttrell LM, Lefkowitz RJ: The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci 2002, 115:455-465.
• [43]Ferrer-Alcon M, La Harpe R, Garcia-Sevilla JA: Decreased immunodensities of micro-opioid receptors, receptor kinases GRK 2/6 and beta-arrestin-2 in postmortem brains of opiate addicts. Brain Res Mol Brain Res 2004, 121:114-122.
• [44]Ontl T, Xing Y, Bai L, Kennedy E, Nelson S, Wakeman M, Magnusson K: Development and aging of N-methyl-D-aspartate receptor expression in the prefrontal/frontal cortex of mice. Neuroscience 2004, 123:467-479.
• [45]Gurevich EV, Benovic JL, Gurevich VV: Arrestin2 expression selectively increases during neural differentiation. J Neurochem 2004, 91:1404-1416.
• [46]Bhargava HN, Gulati A: Down-regulation of brain and spinal cord mu-opiate receptors in morphine tolerant-dependent rats. Eur J Pharmacol 1990, 190:305-311.
• [47]Bernstein MA, Welch SP: mu-Opioid receptor down-regulation and cAMP-dependent protein kinase phosphorylation in a mouse model of chronic morphine tolerance. Brain Res Mol Brain Res 1998, 55:237-242.
• [48]Stafford K, Gomes AB, Shen J, Yoburn BC: mu-Opioid receptor downregulation contributes to opioid tolerance in vivo. Pharmacol Biochem Behav 2001, 69:233-237.
• [49]Koch T, Widera A, Bartzsch K, Schulz S, Brandenburg LO, Wundrack N, Beyer A, Grecksch G, Hollt V: Receptor endocytosis counteracts the development of opioid tolerance. Mol Pharmacol 2005, 67:280-287.
• [50]Haberstock-Debic H, Kim KA, Yu YJ, von Zastrow M: Morphine promotes rapid, arrestin-dependent endocytosis of mu-opioid receptors in striatal neurons. J Neurosci 2005, 25:7847-7857.
• [51]Rodriguez-Munoz M, de la Torre-Madrid E, Gaitan G, Sanchez-Blazquez P, Garzon J: RGS14 prevents morphine from internalizing Mu-opioid receptors in periaqueductal gray neurons. Cell Signal 2007, 19:2558-2571.
• [52]Hara H, Tanaka T, Negoro S, Deguchi Y, Nishio S, Saiki O, Kishimoto S: Age-related changes of expression of IL-2 receptor subunits and kinetics of IL-2 internalization in T cells after mitogenic stimulation. Mech Ageing Dev 1988, 45:167-175.
• [53]Liu L, Turner JR, Yu Y, Khan AJ, Jaszewski R, Fligiel SE, Majumdar AP: Differential expression of EGFR during early reparative phase of the gastric mucosa between young and aged rats. Am J Physiol 1998, 275:G943-950.
• [54]Blanpied TA, Scott DB, Ehlers MD: Age-related regulation of dendritic endocytosis associated with altered clathrin dynamics. Neurobiol Aging 2003, 24:1095-1104.
• [55]Gracy KN, Svingos AL, Pickel VM: Dual ultrastructural localization of mu-opioid receptors and NMDA-type glutamate receptors in the shell of the rat nucleus accumbens. J Neurosci 1997, 17:4839-4848.
• [56]Wang H, Gracy KN, Pickel VM: Mu-opioid and NMDA-type glutamate receptors are often colocalized in spiny neurons within patches of the caudate-putamen nucleus. J Comp Neurol 1999, 412:132-146.
• [57]Commons KG, van Bockstaele EJ, Pfaff DW: Frequent colocalization of mu opioid and NMDA-type glutamate receptors at postsynaptic sites in periaqueductal gray neurons. J Comp Neurol 1999, 408:549-559.
• [58]Mao J, Mayer DJ: Spinal cord neuroplasticity following repeated opioid exposure and its relation to pathological pain. Ann N Y Acad Sci 2001, 933:175-184.
• [59]Taddese A, Nah SY, McCleskey EW: Selective opioid inhibition of small nociceptive neurons. Science 1995, 270:1366-1369.
• [60]Nishizuka Y: Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C. Science 1992, 258:607-614.
• [61]Fan GH, Zhao J, Wu YL, Lou LG, Zhang Z, Jing Q, Ma L, Pei G: N-Methyl-D-aspartate attenuates opioid receptor-mediated G protein activation and this process involves protein kinase C. Mol Pharmacol 1998, 53:684-690.
• [62]Kieffer BL, Evans CJ: Opioid tolerance-in search of the holy grail. Cell 2002, 108:587-590.
• [63]Nicoll RA, Malenka RC: Expression mechanisms underlying NMDA receptor-dependent long-term potentiation. Ann N Y Acad Sci 1999, 868:515-525.
• [64]Ruscheweyh R, Ikeda H, Heinke B, Sandkuhler J: Distinctive membrane and discharge properties of rat spinal lamina I projection neurones in vitro. J Physiol 2004, 555:527-543.
• [65]Ueda H, Inoue M, Mizuno K: New approaches to study the development of morphine tolerance and dependence. Life Sci 2003, 74:313-320.
• [66]Menard DP, van Rossum D, Kar S, Jolicoeur FB, Jhamandas K, Quirion R: Tolerance to the antinociceptive properties of morphine in the rat spinal cord: alteration of calcitonin gene-related peptide-like immunostaining and receptor binding sites. J Pharmacol Exp Ther 1995, 273:887-894.
• [67]Powell KJ, Quirion R, Jhamandas K: Inhibition of neurokinin-1-substance P receptor and prostanoid activity prevents and reverses the development of morphine tolerance in vivo and the morphine-induced increase in CGRP expression in cultured dorsal root ganglion neurons. Eur J Neurosci 2003, 18:1572-1583.
• [68]Zhu H, Barr GA: Opiate withdrawal during development: are NMDA receptors indispensable? Trends Pharmacol Sci 2001, 22:404-408.
• [69]Hoskins B, Ho IK, Meydrech EF: Effects of aging and morphine administration on calmodulin and calmodulin-regulated enzymes in striata of mice. J Neurochem 1985, 44:1069-1073.
• [70]Pascale A, Govoni S, Battaini F: Age-related alteration of PKC, a key enzyme in memory processes: physiological and pathological examples. Mol Neurobiol 1998, 16:49-62.
• [71]Ross EM, Wilkie TM: GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem 2000, 69:795-827.
• [72]Xie GX, Palmer PP: RGS proteins: new players in the field of opioid signaling and tolerance mechanisms. Anesth Analg 2005, 100:1034-1042.
• [73]Singleton MA, Rosen JI, Fisher DM: Pharmacokinetics of fentanyl in the elderly. Br J Anaesth 1988, 60:619-622.
• [74]Ihnatovych I, Novotny J, Haugvicova R, Bourova L, Mares P, Svoboda P: Ontogenetic development of the G protein-mediated adenylyl cyclase signalling in rat brain. Brain Res Dev Brain Res 2002, 133:69-75.
• [75]Burton CK, Ho IK, Hoskins B: Evidence for involvement of cyclic GMP phosphodiesterase in morphine tolerance. J Pharmacol Exp Ther 1990, 252:104-111.
• [76]Grillet N, Dubreuil V, Dufour HD, Brunet JF: Dynamic expression of RGS4 in the developing nervous system and regulation by the neural type-specific transcription factor Phox2b. J Neurosci 2003, 23:10613-10621.
• [77]Ingi T, Aoki Y: Expression of RGS2, RGS4 and RGS7 in the developing postnatal brain. Eur J Neurosci 2002, 15:929-936.
• [78]Gold SJ, Ni YG, Dohlman HG, Nestler EJ: Regulators of G-protein signaling (RGS) proteins: region-specific expression of nine subtypes in rat brain. J Neurosci 1997, 17:8024-8037.
• [79]Wilson LD, Ross SA, Lepore DA, Wada T, Penninger JM, Thomas PQ: Developmentally regulated expression of the regulator of G-protein signaling gene 2 (Rgs2) in the embryonic mouse pituitary. Gene Expr Patterns 2005, 5:305-311.
• [80]Thomas EA, Danielson PE, Sutcliffe JG: RGS9: a regulator of G-protein signalling with specific expression in rat and mouse striatum. J Neurosci Res 1998, 52:118-124.
• [81]Kim KJ, Moriyama K, Han KR, Sharma M, Han X, Xie GX, Palmer PP: Differential expression of the regulator of G protein signaling RGS9 protein in nociceptive pathways of different age rats. Brain Res Dev Brain Res 2005, 160:28-39.
• [82]Stohr J, Bourova L, Hejnova L, Ihnatovych I, Novotny J, Svoboda P: Increased baclofen-stimulated G protein coupling and deactivation in rat brain cortex during development. Brain Res Dev Brain Res 2004, 151:67-73.
• [83]Yu JH, Wieser J, Adams TH: The Aspergillus FlbA RGS domain protein antagonizes G protein signaling to block proliferation and allow development. EMBO J 1996, 15:5184-5190.
• [84]Ingi T, Krumins AM, Chidiac P, Brothers GM, Chung S, Snow BE, Barnes CA, Lanahan AA, Siderovski DP, Ross EM, Gilman AG, Worley PF: Dynamic regulation of RGS2 suggests a novel mechanism in G-protein signaling and neuronal plasticity. J Neurosci 1998, 18:7178-7188.
• [85]Granderath S, Stollewerk A, Greig S, Goodman CS, O'Kane CJ, Klambt C: loco encodes an RGS protein required for Drosophila glial differentiation. Development 1999, 126:1781-1791.
• [86]Wu C, Zeng Q, Blumer KJ, Muslin AJ: RGS proteins inhibit Xwnt-8 signaling in Xenopus embryonic development. Development 2000, 127:2773-2784.
• [87]Tekumalla PK, Calon F, Rahman Z, Birdi S, Rajput AH, Hornykiewicz O, Di Paolo T, Bedard PJ, Nestler EJ: Elevated levels of DeltaFosB and RGS9 in striatum in Parkinson's disease. Biol Psychiatry 2001, 50:813-816.
• [88]Muma NA, Mariyappa R, Williams K, Lee JM: Differences in regional and subcellular localization of G(q/11) and RGS4 protein levels in Alzheimer's disease: correlation with muscarinic M1 receptor binding parameters. Synapse 2003, 47:58-65.
• [89]Van Crugten JT, Somogyi AA, Nation RL, Reynolds G: The effect of old age on the disposition and antinociceptive response of morphine and morphine-6 beta-glucuronide in the rat. Pain 1997, 71:199-205.
• [90]Minto CF, Schnider TW, Egan TD, Youngs E, Lemmens HJ, Gambus PL, Billard V, Hoke JF, Moore KH, Hermann DJ, Muir KT, Mandema JW, Shafer SL: Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I. Model development. Anesthesiology 1997, 86:10-23.
• [91]Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH: Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth 2004, 92:208-217.
• [92]Bhargava HN, Villar VM, Rahmani NH, Larsen AK: Studies on the possible role of pharmacokinetics in the development of tolerance to morphine in the rat. Gen Pharmacol 1992, 23:1199-1204.
• [93]Gardell LR, King T, Ossipov MH, Rice KC, Lai J, Vanderah TW, Porreca F: Opioid receptor-mediated hyperalgesia and antinociceptive tolerance induced by sustained opiate delivery. Neurosci Lett 2006, 396:44-49.