Opioids pp 625-643 | Cite as

Interrelationships of Opioid, Dopaminergic, Cholinergic, and GABAergic Pathways in the Central Nervous System

  • P. L. Wood
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 104 / 1)


It is the purpose of this chapter to give an overview of the complex interactions between endogenous opioid, dopaminergic, cholinergic, and GABAergic pathways in the brain. The effects described involve both acute and long-term adaptive changes as well as reciprocal interactions. Within this complex framework some general principles will evolve; however, as with so many other CNS pathways, there are species differences which require definition to demonstrate the limits of apparent generalizations. While this review will focus on neurochemical indices of CNS functional changes it is pharmacologically induced alterations which will be summarized; therefore, whenever possible studies of both dose-response and time course relationships will be referenced.


Nucleus Accumbens Opioid Receptor Opioid Peptide Opiate Receptor Cholinergic Pathway 
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  1. Ahtee L, Kaariainen I (1973) The effect of narcotic analgesics on the homovanillic acid content of rat nucleus caudatus. Eur J Pharmacol 22: 206–208PubMedCrossRefGoogle Scholar
  2. Akil H, Hewlett WA, Barchas JD, Li CH (1980) Binding of 3H-β-endorphin to rat brain membranes: characterization of opiate receptors and interaction with ACTH. Eur J Pharmacol 64: 1–8PubMedCrossRefGoogle Scholar
  3. Algeri S, Brunello N, Calderini A, Consolazione A (1978) Effect of enkephalins on catecholamine metabolism in rat CNS. Adv Biochem Psychopharmacol 18: 199–210PubMedGoogle Scholar
  4. Angulo JA, Cadet JL, Woolley CS, Suber F, McEwen BS (1990) Effect of chronic typical and atypical neuroleptic treatment on proenkephalin mRNA levels in the striatum and nucleus accumbens of the rat. J Neurochem 54: 1889–1894PubMedCrossRefGoogle Scholar
  5. Beck T, Krieglstein J (1986) The effects of tifluadom and ketazocine on behavior, dopamine turnover in the basal ganglia and local cerebral glucose utilization of rats. Brain Res 381: 327–335PubMedCrossRefGoogle Scholar
  6. Biggio G, Casu M, Corda MG, Di Bello C, Gessa GL (1978) Stimulation of dopamine synthesis in caudate nucleus by intrastriatal enkephalins and antagonism by naloxone. Science 200: 552–554PubMedCrossRefGoogle Scholar
  7. Bloom FE, Rossier J, Batenberg ELF, Bayon A, French E, Hendrickson SJ, Siggins GR, Segal D, Browne R, Ling N, Guillemin R (1978) Beta endorphin: cellular localization, electrophysiological and behavioral effects. Adv Biochem Psychopharmacol 18: 89–109PubMedGoogle Scholar
  8. Bozarth MA, Wise RA (1981) Intracranial self-administration of morphine into the ventral tegmental area in rats. Life Sci 28: 551–555PubMedCrossRefGoogle Scholar
  9. Bozarth MA, Wise RA (1984) Anatomically distinct opiate receptor fields mediate reward and physical dependence. Science 244: 516–517CrossRefGoogle Scholar
  10. Carenzi A, Cheney DL, Costa E, Guidotti A, Racagni G (1975) Actions of opiates, antipsychotics, amphetamine and apomorphine on dopamine receptors in rat striatum: in vivo changes of 3’,5’-cyclic AMP content and acetylcholine turnover rate. Neuropharmacology 14: 927–939PubMedCrossRefGoogle Scholar
  11. Cheney DL, Trabucchi M, Racagni G, Wang C, Costa E (1974) Effects of acute and chronic morphine on regional rat brain acetylcholine turnover rate. Life Sci 15:1977Google Scholar
  12. Cheney DL, Trabucchi M, Racagni G, Wang C, Costa E (1975) An analysis at the synaptic level of the morphine action in striatum and N. accumbens, dopamine and acetylcholine interaction. Life Sci 17: 1–8Google Scholar
  13. Cheney DL, Lehmann J, Cosi C, Wood PL (1989) Determination of acetylcholine dynamics. Neuromethods 12: 443–495Google Scholar
  14. Collu RE, Stefanini E, Vernaleone F, Marchisio AM, Devoto P, Argiolas A (1980) Biochemical characterization of the dopaminergic innervation of the rat septum. Life Sci 26: 1665–1673PubMedCrossRefGoogle Scholar
  15. Costa E, Panula P, Thompson HK, Cheney DL (1983) The transsynaptic regulation of the septal-hippocampal cholinergic neurons. Life Sci 32: 165–179PubMedCrossRefGoogle Scholar
  16. Di Chiara G, Imperato A (1988a) Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats. J Pharmacol Exp Ther 244: 1067–1080PubMedGoogle Scholar
  17. Di Chiara G, Imperato A (1988b) Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats. Proc Natl Acad Sci USA 85: 5274–5278PubMedCrossRefGoogle Scholar
  18. Dourmap N, Michael-Titus A, Costentin J (1990) Local enkephalins tonically modulate dopamine release in the striatum: a microdialysis study. Brain Res 524: 153–155PubMedCrossRefGoogle Scholar
  19. Duka T, Wuster M, Herz A (1980) Benzodiazepines modulate striatal enkephalin levels via a GABergic mechanism. Life Sci 26: 771–776PubMedCrossRefGoogle Scholar
  20. Gale K, Moroni F, Kumakura K, Guidotti A (1979) Opiate receptors in substantia nigra: role in the regulation of striatal tyrosine hydroxylase. Neuropharmacology 18: 427–430PubMedCrossRefGoogle Scholar
  21. Groppetti A, Algeri S, Cattabeni F, DiGiulio AM, Galli CL, Ponzio F, Spano PF (1977) Changes in specific activity of dopamine metabolites as evidence of a multiple compartmentation of dopamine in striatal neurons. J Neurochem 28: 193–197PubMedCrossRefGoogle Scholar
  22. Hanson GR, Merchant KM, Letter AA, Bush L, Gibb JW (1987) Methamphetamine- induced changes in the striatal-nigral dynorphin system: role of D-l and D-2 receptors. Eur J Pharmacol 144: 245–246PubMedCrossRefGoogle Scholar
  23. Höllt V (1986) Opioid peptide processing and receptor selectivity. Annu Rev Pharmacol Toxicol 26: 59–72PubMedCrossRefGoogle Scholar
  24. Hong JS, Yang H YT, Fratta W, Costa E (1978) Rat striatal methionine–enkephalin content after chronic treatment with cataleptogenic and noncataleptogenic antischizophrenic drugs. J Pharmacol Exp Ther 205: 141–147PubMedGoogle Scholar
  25. Houdi AA, Van Loon GR (1990) Haloperidol–induced increase in striatal concentration of the tripeptide, Tyr-Gly-Gly, provides an index of increased enkephalin release in vivo. J Neurochem 54: 1360–1366Google Scholar
  26. Iyengar S, Wood PL (1989) Multiplicity and classification of opioid receptors. In: Szekely JI, Ramabadran K (eds) Opioid peptides, vol 4. CRC Press, Boca Raton, pp 115–132Google Scholar
  27. Iyengar S, Kim HS, Wood PL (1987a) Agonist action of the agonist/antagonist analgesic butorphanol on dopamine metabolism in the nucleus accumbens of the rat. Neurosci Lett 77: 226–230PubMedCrossRefGoogle Scholar
  28. Iyengar S, Kim HS, Wood PL (1987b) Effects of kappa opiate agonists on neurochemical and neuroendocrine indices: evidence for kappa receptor subtypes. Life Sci 39: 637–644CrossRefGoogle Scholar
  29. Iyengar S, Kim HS, Marien M, McHugh D, Wood PL (1989) Modulation of mesolimbic dopaminergic projections by β-endorphin in the rat. Neuropharmacology 28: 123–128PubMedCrossRefGoogle Scholar
  30. Jhamandas K, Sutak M (1976) Morphine-naloxone interaction in the central cholinergic system: the influence of subcortical lesioning and electrical stimulation. Br J Pharmacol 58: 101–107PubMedGoogle Scholar
  31. Jhamandas K, Hron V, Sutak M (1975) Comparative effects of opiate agonists methadone, levorphanol and their isomers on the release of cortical ACH in vivo and in vitro. Can J Physiol Pharmacol 50: 57–62Google Scholar
  32. Jiang H K, McGinty JF, Hong JS (1990) Differential modulation of striatonigral dynorphin and enkephalin by dopamine receptor subtypes. Brain Res 507: 57–64PubMedCrossRefGoogle Scholar
  33. Kim HS, Iyengar S, Wood PL (1986a) Opiate actions of mesocortical dopamine metabolism in the rat. Life Sci 39: 2033–2036PubMedCrossRefGoogle Scholar
  34. Kim HS, Iyengar S, Wood PL (1986b) Reversal of the actions of morphine on mesocortical dopamine metabolism in the rat by the kappa agonist MR-2034: tentative mu-2 opioid control of mesocortical dopaminergic projections. Life Sci 41: 1711–1715CrossRefGoogle Scholar
  35. Kuschinsky K, Hornykiewicz O (1974) Effects of morphine on striatal dopamine metabolism: possible mechanism of its opposite effect on locomotor activity in rats and mice. Eur J Pharmacol 26: 41–50PubMedCrossRefGoogle Scholar
  36. Li SJ, Jiang HK, Stachowiak MS, Hudson PM, Owyang V, Nanry K, Tilson HA, Hong JS (1990) Influence of nigrostriatal dopaminergic tone on the biosynthesis of dynorphin and enkephalin in rat striatum. Mol Brain Res 8: 219–225PubMedCrossRefGoogle Scholar
  37. Llorens-Cortes C, Pollard H, Schwartz JC (1979) Localization of opiate receptors in substantia nigra evidence by lesion studies. Neurosci Lett 12: 165–170PubMedCrossRefGoogle Scholar
  38. Llorens-Cortes C, Schwartz J-C (1984) Changes in turnover of cerebral monoamines following inhibition of enkephalin metabolism by thiorphan and bestatin. Eur J Pharmacol 104: 369–374PubMedCrossRefGoogle Scholar
  39. Llorens–Cortes C, Van Amsterdam JGC, Giros B, Quach TT, Schwartz JC (1990) Enkephalin biosynthesis and release in mouse striatum are inhibited by GABA receptor stimulation: compared changes in preproenkephalin mRNA and Tyr- Gly-Gly levels. Mol Brain Res 8: 227–233CrossRefGoogle Scholar
  40. Martin WR (1967) Opioid antagonists. Pharmacol Rev 19: 463–521PubMedGoogle Scholar
  41. Mocchetti I, Schwartz JP, Costa E (1985) Use of mRNA hybridization and radioimmunoassay to study mechanisms of drug-induced accumulation of enkephalins in rat brain structures. Mol Pharmacol 28: 86–91PubMedGoogle Scholar
  42. Moroni F, Cheney DL, Costa E (1977) Inhibition of acetylcholine turnover in rat hippocampus by intraseptal injections of β–endorphin and morphine. Naunyn Schmiedebergs Arch Exp Pharmacol 299: 149–153CrossRefGoogle Scholar
  43. Moroni F, Cheney DL, Peralta E, Costa E (1978) Opiate receptor agonists as modulators of gamma–aminobutyric acid turnover in the nucleus caudatus, globus pallidus and substantia nigra of the rat. J Pharmacol Exp Ther 207: 870–877PubMedGoogle Scholar
  44. Moroni F, Peralta E, Cheney DL, Costa E (1979) On the regulation of gamma- aminobutyric acid neurons in caudatus, pallidus and nigra: effects of opioids and dopamine agonists. J Pharmacol Exp Ther 208: 190–194PubMedGoogle Scholar
  45. Morris BJ, Reimer S, Höllt V, Herz A (1988a) Regulation of striatal prodynorphin mRNA levels by the raphe-striatal pathway. Mol Brain Res 4: 15–22CrossRefGoogle Scholar
  46. Morris BJ, Höllt V, Herz A (1988b) Opioid gene expression in rat striatum is modulated via opioid receptors: evidence from localized receptor inactivation. Neurosci Lett 89:80–84 Pasternak GW, Wood PL (1986) Minireview: multiple mu opioid receptors. Life Sci 38: 1889–1898Google Scholar
  47. Pepeu G (1973) The release of acetylcholine from the brain: an approach to the study of the central cholinergic mechanisms. Prog Neurobiol 2: 259–288PubMedCrossRefGoogle Scholar
  48. Petrack B, Emmett MR, Rao JT, Kim HS, Wood PL (1990) Increases in rat striatal preproenkephalin mRNA levels following chronic treatment with the depot neuroleptic, haloperidol decanoate. Life Sci 46: 687–691PubMedCrossRefGoogle Scholar
  49. Pollard H, Llorens C, Bonnet JJ, Costentin J, Schwartz JC (1977) Opiate receptors on mesolimbic dopaminergic neurons. Neurosci Lett 7: 295–299CrossRefGoogle Scholar
  50. Racagni C, Bruno F, Iuliano E, Paoletti R (1979) Differential sensitivity to behavioral and biochemical correlations. J Pharmacol Exp Ther 209:111–116Google Scholar
  51. Rackham A, Wood PL, Hudgin RL (1982) Kyotorphan (tyrosine– arginine): further evidence for indirect opiate receptor activation. Life Sci 30: 1337–1342PubMedCrossRefGoogle Scholar
  52. Reid MS, O’Connor WT, Herrera-Marschitz M, Ungerstedt U (1990) The effects of intranigral GABA and dynorphin A injections on striatal dopamine and GABA release: evidence that dopamine provides inhibitory regulation of striatal GABA neurons via D2 receptors. Brain Res 519: 255–260PubMedCrossRefGoogle Scholar
  53. Schwartz JP, Costa E (1986) Hybridization approaches to the study of neuropeptides. Annu Rev Neurosci 9: 277–304PubMedCrossRefGoogle Scholar
  54. Sivam SP, Hong JS (1986) GABAergic regulation of enkephalin in rat striatum: alterations in Met5-enkephalin, precursor content and preproenkephalin messenger RNA abundance. J Pharmacol Exp Ther 237: 326–331PubMedGoogle Scholar
  55. Smith CB, Sheldon MT, Bednarczyk JH, Villarreal JE (1972) Morphine-induced increases in the incorporation of 14C–tyrosine into 14C-dopamine and 14C- norepinephrine in the mouse brain: antagonism by naloxone and tolerance. J Pharmacol Exp Ther 180: 547–557PubMedGoogle Scholar
  56. Spanagel R, Herz A, Shippenberg TS (1990) Identification of the opioid receptor types mediating β–endorphin-induced alterations in dopamine release in the nucleus accumbens. Eur J Pharmacol 190: 177–184PubMedCrossRefGoogle Scholar
  57. Szerb J (1974) Lack of effect of morphine in reducing the release of labelled acetylcholine from brain slices stimulated electrically. Eur J Pharmacol 29: 192–194PubMedCrossRefGoogle Scholar
  58. Tempel A, Kessler JA, Zukin RS (1990) Chronic naltrexone treatment increases expression of preproenkephalin and preprotachykinin mRNA in discrete brain regions. J Neurosci 10: 741–747PubMedGoogle Scholar
  59. Thai LJ, Sharpless NS, Hirschhorn ID, Horowitz SG, Makman MH (1983) Striatal met-enkephalin increases following nigrostriatal denervation. Biochem Pharmacol 32: 3297–3301CrossRefGoogle Scholar
  60. Uhl GR, Ryan JP, Schwartz JP (1988a) Morphine alters preproenkephalin gene expression. Brain Res 100: 391–397CrossRefGoogle Scholar
  61. Uhl GR, Navia B, Douglas J (1988b) Differential expression of preproenkephalin and preprodynorphin mRNAs in striatal neurons: high levels of preproenkephalin expression depend on cerebral cortical afferents. J Neurosci 8: 4755–4764PubMedGoogle Scholar
  62. Vincent S, Hokfelt T, Christensson I, Terenius L (1982) Immunohistochemical evidence for a dynorphin immunoreactive striato-nigral pathway. Eur J Pharmacol 85: 251–252PubMedCrossRefGoogle Scholar
  63. Watson SJ, Barchas JD (1979) Anatomy of the endogenous opioid peptides and related substances: the enkephalins, β-endorphin, β-lipotropin and ACTH. In: Beers RF, Bassett EG (eds) Mechanisms of pain and analgesic compounds. Raven, New York, p 227Google Scholar
  64. Wenzel J, Kuschinsky K (1990) Effects of morphine on gamma-aminobutyric acid turnover in the basal gamglia. Possible correlation with its biphasic action on motility. Arzneimittelforschung 40: 811–813Google Scholar
  65. Westerink BHC (1978) Effect of centrally acting drugs on regional dopamine metabolism. Adv Biochem Psychopharmacol 19: 255–266PubMedGoogle Scholar
  66. Wood PL (1982) Phasic enkephalinergic modulation of nigrostriatal dopamine metabolism: potentiation with enkephalinase inhibitors. Eur J Pharmacol 82: 119–120PubMedCrossRefGoogle Scholar
  67. Wood PL (1983) Opioid regulation of CNS dopaminergic pathways: a review of methodology, receptor types, regional variations and species differences. Peptides 4: 595–601PubMedCrossRefGoogle Scholar
  68. Wood PL (1984) Kappa agonist analgesics: evidence for mu-2 and delta receptor antagonism. Drug Dev Res 4: 429–435CrossRefGoogle Scholar
  69. Wood PL (1986) Pharmacological evaluation of GABAergic and glutamatergic inputs to the nucleus basalis - cortical and the septal - hippocampal cholinergic projections. Can J Physiol Pharmacol 64: 325–328PubMedCrossRefGoogle Scholar
  70. Wood PL (1988) The significance of multiple CNS opioid receptor types: a review of critical considerations relating to technical details and anatomy in the study of central opioid actions. Peptides 9: 49–55PubMedCrossRefGoogle Scholar
  71. Wood PL, Altar CA (1988) Dopamine release in vivo from nigrostriatal, mesolimbic, and mesocortical neurons: utility of 3-methoxytyramine measurements. Pharmacol Rev 40: 163–187PubMedGoogle Scholar
  72. Wood PL, Cheney DL (1985) Gas chromatography-mass fragmentography of amino acids. Neuromethods 3: 51–80Google Scholar
  73. Wood PL, Cosi C (1987) Kappa receptor modulation of the nigrocollicular GABA pathway in the rat. Soc Neurosci Abstr 13: 402. 10Google Scholar
  74. Wood PL, Iyengar S (1986) Kappa isoreceptors: neurochemical and neuroendocrine evidence. NIDA Monogr 71: 102–108Google Scholar
  75. Wood PL, Iyengar S (1988) Central actions of opiates and opioid peptides: in vivo evidence for opioid receptor multiplicity. In: Pasternak GW (ed) The opiate receptors. Humana Press, Clifton, pp 307–356Google Scholar
  76. Wood PL, McQuade P (1986) Substantia innominata cortical cholinergic pathway: regulatory afferents. Adv Behav Biol 30: 999–1006Google Scholar
  77. Wood PL, Pasternak GW (1983) Specific mu-2 opioid iso-receptor regulation of nigrostriatal neurons: in vivo evidence with naloxonazine. Neurosci Lett 37: 291–293PubMedCrossRefGoogle Scholar
  78. Wood PL, Rackham A (1981) Actions of kappa, sigma and partial mu narcotic receptor agonists on rat brain acetylcholine turnover. Neurosci Lett 23: 75–80PubMedCrossRefGoogle Scholar
  79. Wood PL, Rao TS (1991) Morphine stimulation of mesolimbic and mesocortical but not nigrostriatal dopamine release in the rat as reflected by changes in 3-methoxytyramine levels. Neuropharmacology 30: 399–401PubMedCrossRefGoogle Scholar
  80. Wood PL, Richard JW (1982a) Morphine and nigrostriatal function in the rat and mouse: the role of nigral and striatal opiate receptors. Neuropharmacology 21: 1305–1310PubMedCrossRefGoogle Scholar
  81. Wood PL, Richard J (1982b) GABAergic regulation of the substantia innominate- cortical cholinergic pathway. Neuropharmacology 21: 969–972PubMedCrossRefGoogle Scholar
  82. Wood PL, Stotland LM (1980) Actions of enkephalin, mu and partial agonist analgesics on acetylcholine turnover in rat brain. Neuropharmacology 19: 975–982PubMedCrossRefGoogle Scholar
  83. Wood PL, Cheney DL, Costa E (1979) An investigation of whether septal β- aminobutyrate-containing interneurons are involved in the reduction of the turnover rate of acetylcholine elicited by substance P and β–endorphin in the hippocampus. Neuroscience 4: 1479–1484PubMedCrossRefGoogle Scholar
  84. Wood PL, Sotland M, Richard JW, Rackham A (1980) Actions of mu, kappa, sigma, delta, and agonist/antagonist opiates on striatal dopaminergic function. J Pharmacol Exp Ther 215: 697–703PubMedGoogle Scholar
  85. Wood PL, Richard JW, Thakur M (1982) Mu opiate isoreceptors: differentiation with kappa agonists. Life Sci 31: 2313–2317PubMedCrossRefGoogle Scholar
  86. Wood PL, Sanschagrin D, Richard JW, Thakur M (1983a) Multiple receptor affinities of kappa and agonist/antagonist analgesics: in vivo assessment. J Pharmacol Exp Ther 226: 545–550PubMedGoogle Scholar
  87. Wood PL, McQuade P, Richard JW, Thakur M (1983b) Agonist/antagonist analgesics and nigrostriatal dopamine metabolism in the rat: evidence for receptor dualism. Life Sci 33: 759–762PubMedCrossRefGoogle Scholar
  88. Wood PL, Stotland LM, Racham A (1984a) Opiate receptor regulation of acetylcholine metabolism: role of mu, delta, kappa and sigma receptors. In: Hanin I (ed) Dynamics of neurotransmitter function. Raven, New York, pp 99–107Google Scholar
  89. Wood PL, Pilapil C, Thakur M, Richard JW (1984b) WIN 44,441: a stereospecific and long–acting narcotic antagonist. Pharsm Res 1: 46–48CrossRefGoogle Scholar
  90. Wood PL, McQuade PS, Nair NPV (1984c) GABAergic and opioid regulation of the substantia innominate-cortical cholinergic pathway in the rat. Prog Neuro- psychopharmacol Biol Psychiatry 8: 789–792CrossRefGoogle Scholar
  91. Wood PL, Kim HS, Cosi C, Iyengar S (1987a) The endogenous kappa agonist, dynorphin (1–13), does not alter basal or morphine-stimulated dopamine metabolism in the nigrostriatal pathway of the rat. Neuropharmacology 26: 1585–1588PubMedCrossRefGoogle Scholar
  92. Wood PL, Kim HS, Altar CA (1987b) In vivo assessment of dopamine and norepinephrine release in rat neocortex: GC-MF measurement of 3- methoxytyramine (3-MT) and normetanephrine ( NMN ). J Neurochem 48: 574–579Google Scholar
  93. Wood PL, Kim HS, Marien MR (1987c) Intracerebral dialysis: direct evidence for the utility of 3–MT measurements as an index of dopamine release. Life Sci 41: 1–5PubMedCrossRefGoogle Scholar
  94. Wood PL, Kim HS, Cheney DL, Cosi C, Marien M, Rao TS, Martin LL (1988) Constant infusion of [13C6]glucose: simultaneous measurement of GABA and glutamate turnover in defined rat brain regions of single animals. Neuropharmacology 27: 669–676PubMedCrossRefGoogle Scholar
  95. Wüster M, Duka T, Herz A (1980) Diazepam effects on striatal Met-enkephalin levels following long-term pharmacological manipulations. Neuropharmacology 19: 501–505PubMedCrossRefGoogle Scholar
  96. Yonehara N, Clouet DH (1984) Effects of delta and mu opiopeptides on the turnover and release of dopamine in rat striatum. J Pharmacol Exp Ther 231: 38–42PubMedGoogle Scholar
  97. Zsilla G, Cheney DL, Racagni G, Costa E (1976) Correlation between analgesia and the decrease of acetylcholine turover rate in cortex and hippocampus elicited by morphine, meperidine, viminol R2 and azidomorphine. J Pharmacol Exp Ther 199: 662–668PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1993

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  • P. L. Wood

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