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FAAH selectively influences placebo effects

Molecular Psychiatry volume 19, pages 385–391 (2014)Cite this article

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Abstract

Endogenous opioid and cannabinoid systems are thought to act synergistically regulating antinociceptive and reward mechanisms. To further understand the human implications of the interaction between these two systems, we investigated the role of the common, functional missense variant Pro129Thr of the gene coding fatty acid amide hydrolase (FAAH), the major degrading enzyme of endocannabinoids, on psychophysical and neurotransmitter (dopaminergic, opioid) responses to pain and placebo-induced analgesia in humans. FAAH Pro129/Pro129 homozygotes, who constitute nearly half of the population, reported higher placebo analgesia and more positive affective states immediately and 24 h after placebo administration; no effects on pain report in the absence of placebo were observed. Pro129/Pro129 homozygotes also showed greater placebo-induced μ-opioid, but not D2/3 dopaminergic, enhancements in neurotransmission in regions known involved in placebo effects. These results show that a common genetic variation affecting the function of the cannabinoid system is serving as a probe to demonstrate the involvement of cannabinoid and opioid transmitters on the formation of placebo effects.

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References

  1. Zubieta JK et al. Placebo effects mediated by endogenous opioid activity on mu-opioid receptors. J Neurosci 2005; 25: 7754–7762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Amanzio M, Benedetti F . Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems. J Neurosci 1999; 19: 484–494.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kogan NM, Mechoulam R . The chemistry of endocannabinoids. J EndocrinolI Invest 2006; 29 (3 Suppl): 3–14.

    CAS  Google Scholar 

  4. Hohmann AG . Spinal and peripheral mechanisms of cannabinoid antinociception: behavioral, neurophysiological and neuroanatomical perspectives. Chem Phys Lipids 2002; 121: 173–190.

    Article  CAS  PubMed  Google Scholar 

  5. Gardner EL, Vorel SR . Cannabinoid transmission and reward-related events. Neurobiol Dis 1998; 5 (6 Pt B): 502–533.

    Article  CAS  PubMed  Google Scholar 

  6. Colloca L, Sigaudo M, Benedetti F . The role of learning in nocebo and placebo effects. Pain 2008; 136: 211–218.

    Article  CAS  PubMed  Google Scholar 

  7. Benedetti F, Amanzio M, Rosato R, Blanchard C . Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors. Nat Med 2011; 17: 1228–1230.

    Article  CAS  PubMed  Google Scholar 

  8. Salio C, Fischer J, Franzoni MF, Mackie K, Kaneko T, Conrath M . CB1-cannabinoid and mu-opioid receptor co-localization on postsynaptic target in the rat dorsal horn. Neuroreport 2001; 12: 3689–3692.

    Article  CAS  PubMed  Google Scholar 

  9. Ledent C et al. Unresponsiveness to cannabinoids and reduced addictive effects of opiates in CB1 receptor knockout mice. Science 1999; 283: 401–404.

    Article  CAS  PubMed  Google Scholar 

  10. Welch SP . Interaction of the cannabinoid and opioid systems in the modulation of nociception. Int Rev Psychiatry 2009; 21: 143–151.

    Article  PubMed  Google Scholar 

  11. Haller VL, Stevens DL, Welch SP . Modulation of opioids via protection of anandamide degradation by fatty acid amide hydrolase. Eur J Pharmacol 2008; 600: 50–58.

    Article  CAS  PubMed  Google Scholar 

  12. Wilson RI, Nicoll RA . Endocannabinoid signaling in the brain. Science 2002; 296: 678–682.

    Article  CAS  PubMed  Google Scholar 

  13. Chiang KP, Gerber AL, Sipe JC, Cravatt BF . Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use. Hum Mol Genet 2004; 13: 2113–2119.

    Article  CAS  PubMed  Google Scholar 

  14. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK . Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 2008; 65: 220–231.

    Article  PubMed  Google Scholar 

  15. Zubieta JK et al. Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science 2001; 293: 311–315.

    Article  CAS  PubMed  Google Scholar 

  16. De Vries TJ et al. A cannabinoid mechanism in relapse to cocaine seeking. Nat Med 2001; 7: 1151–1154.

    Article  CAS  PubMed  Google Scholar 

  17. Lesscher HM, Hoogveld E, Burbach JP, van Ree JM, Gerrits MA . Endogenous cannabinoids are not involved in cocaine reinforcement and development of cocaine-induced behavioural sensitization. Eur Neuropsychopharmacol 2005; 15: 31–37.

    Article  CAS  PubMed  Google Scholar 

  18. Hodgkinson CA et al. Addictions biology: haplotype-based analysis for 130 candidate genes on a single array. Alcohol Alcohol 2008; 43: 505–515.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stohler CS, Kowalski CJ . Spatial and temporal summation of sensory and affective dimensions of deep somatic pain. Pain 1999; 79: 165–173.

    Article  CAS  PubMed  Google Scholar 

  20. Watson D, Clark LA, Tellegen A . Development and validation of brief measures of positive and negative affect: the PANAS scales. J Pers Soc Psychol 1988; 54: 1063–1070.

    Article  CAS  PubMed  Google Scholar 

  21. Pollock V, Cho DW, Reker D, Volavka J . Profile of Mood States: the factors and their physiological correlates. J Nervous Mental Dis 1979; 167: 612–614.

    Article  CAS  Google Scholar 

  22. Melzack R, Torgerson WS . On the language of pain. Anesthesiology 1971; 34: 50–59.

    Article  CAS  PubMed  Google Scholar 

  23. Jewett DM . A simple synthesis of [11C]carfentanil using an extraction disk instead of HPLC. Nuclear Med Biol 2001; 28: 733–734.

    Article  CAS  Google Scholar 

  24. Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL . Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cerebral Blood Flow Metab 1996; 16: 834–840.

    Article  CAS  Google Scholar 

  25. Narendran R, Martinez D . Cocaine abuse and sensitization of striatal dopamine transmission: a critical review of the preclinical and clinical imaging literature. Synapse 2008; 62: 851–869.

    Article  CAS  PubMed  Google Scholar 

  26. Martin M, Ledent C, Parmentier M, Maldonado R, Valverde O . Cocaine, but not morphine, induces conditioned place preference and sensitization to locomotor responses in CB1 knockout mice. Eur J Neurosci 2000; 12: 4038–4046.

    Article  CAS  PubMed  Google Scholar 

  27. Adcock RA, Thangavel A, Whitfield-Gabrieli S, Knutson B, Gabrieli JD . Reward-motivated learning: mesolimbic activation precedes memory formation. Neuron 2006; 50: 507–517.

    Article  CAS  PubMed  Google Scholar 

  28. Pecina M, Stohler CS, Zubieta JK . Role of mu-opioid system in the formation of memory of placebo responses. Mol Psychiatry 2012; 18: 135–137.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Cravatt BF et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 2001; 98: 9371–9376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sim LJ, Selley DE, Xiao R, Childers SR . Differences in G-protein activation by mu- and delta-opioid, and cannabinoid, receptors in rat striatum. Eur J Pharmacol 1996; 307: 97–105.

    Article  CAS  PubMed  Google Scholar 

  31. Sim-Selley LJ, Martin BR . Effect of chronic administration of R-(+)-[2,3-Dihydro–5-methyl–3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]–1,4-benzoxaz inyl]-(1-naphthalenyl)methanone mesylate (WIN55,212–2) or delta(9)-tetrahydrocannabinol on cannabinoid receptor adaptation in mice. J Pharmacol Exp Ther 2002; 303: 36–44.

    Article  CAS  PubMed  Google Scholar 

  32. Rice OV, Gordon N, Gifford AN . Conditioned place preference to morphine in cannabinoid CB1 receptor knockout mice. Brain Res 2002; 945: 135–138.

    Article  CAS  PubMed  Google Scholar 

  33. Mas-Nieto M et al. Reduction of opioid dependence by the CB(1) antagonist SR141716A in mice: evaluation of the interest in pharmacotherapy of opioid addiction. Br J Pharmacol 2001; 132: 1809–1816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Navarro M et al. Functional interaction between opioid and cannabinoid receptors in drug self-administration. J Neurosci 2001; 21: 5344–5350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Di Marzo V . Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov 2008; 7: 438–455.

    Article  CAS  PubMed  Google Scholar 

  36. Naidu PS, Kinsey SG, Guo TL, Cravatt BF, Lichtman AH . Regulation of inflammatory pain by inhibition of fatty acid amide hydrolase. J Pharmacol Exp Ther 2010; 334: 182–190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fattore L, Vigano D, Fadda P, Rubino T, Fratta W, Parolaro D . Bidirectional regulation of mu-opioid and CB1-cannabinoid receptor in rats self-administering heroin or WIN 55,212–2. Eur J Neurosci 2007; 25: 2191–2200.

    Article  PubMed  Google Scholar 

  38. Fattore L et al. Endocannabinoid system and opioid addiction: behavioural aspects. Pharmacol Biochem Behav 2005; 81: 343–359.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We wish to acknowledge the nuclear medicine technologists of the PET Center at the University of Michigan for the assistance in PET data acquisition and reconstruction. Funding: work was supported by R01 DA 022520, R01 DA027494 and the Phil F Jenkins Foundation (JKZ). MMJ was supported by the Spanish Ministry of Education (MMJ: AP2008–03742).

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Authors and Affiliations

  1. Department of Psychiatry, University of Michigan, Ann Arbor, MI, USA

    M Peciña & J K Zubieta

  2. Research Institute on Health Sciences—IUNICS, Palma de Mallorca, Spain

    M Martínez-Jauand

  3. Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA

    C Hodgkinson & D Goldman

  4. School of Dentistry, University of Maryland, Baltimore, MD, USA

    C S Stohler

  5. Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, USA

    J K Zubieta

  6. Department of Radiology, University of Michigan, Ann Arbor, MI, USA

    J K Zubieta

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  1. M Peciña
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  2. M Martínez-Jauand
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  3. C Hodgkinson
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  4. C S Stohler
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Correspondence to J K Zubieta.

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The authors declare no conflict of interest.

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Author contributions

JKZ, CSS and DG were responsible for the study design and procured the study funding; JKZ and CSS collected data; MP, MMJ and CH analyzed the data; MP and JKZ wrote the manuscript.

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Peciña, M., Martínez-Jauand, M., Hodgkinson, C. et al. FAAH selectively influences placebo effects. Mol Psychiatry 19, 385–391 (2014). https://doi.org/10.1038/mp.2013.124

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