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A brief presentation on endocannabinoids, the neural circuitry, the neurochemistry, clinical presentations and its links, among others.

Publicada em: Saúde e medicina
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  1. 1. Dr.Samin Sameed Psychiatrist, KIMS HOSPITAL KOCHI,Kerala contact- 9743474568
  2. 2.  Cannabinoids are a group of chemicals which activate the body’s cannabinoid receptors. Endogenous Herbal Synthetic
  3. 3. History  Medicinal use of Cannabis described by Chinese emperor Shen Nung (2700BC)
  4. 4.  1899- Cannabinol isolated from cannabis resin  1964- discovery of structure of D9- THC  1990- brain cannabinoid receptor, CB1.  1992- Anandamide  1994- CB2
  5. 5.  1994- Rimonabant –CB1 blocker.  1995- 2-AG  1996- FAAH discovered.
  6. 6. Raphael Mechoulam and Yeheel Gaoni Raphael Mechoulam
  7. 7. Getting high!  Cannabis acting on a neural pathway involving cannabinoids endogenous to the human brain ENDOCANNABINOIDS
  8. 8.  THC acid is the predominant form of the plant THC, and this is readily converted to THC upon heating, such as when cannabis is smoked.  Estimates suggest that 20 to 80 µg of THC reach the brain after one smokes a marijuana cigarette
  9. 9. Endocannabinoids
  10. 10. Anandamide  Mimic THC  Inhibition of spontaneous movement  Reduces pain sensitivity  Decreases body temperature.
  11. 11. Others  2-arachidonylglycerol (2-AG)  N-arachidonyldopamine (NADA)  2-arachidonoyl glycerol ether (noladin ether),  Virodhamine
  12. 12. Bio synthesis  Arachidonic acid -building block  Endocannabinoids are not stored in synaptic vesicles for later use, but are synthesized on demand  Endocannabinoids are highly lipophilic and thus poorly soluble in cerebrospinal fluid (CSF)
  13. 13.  Converts anandamide to arachidonic acid and ethanolamine  Found in regions of the brain where CB1 receptors are predominant  Inhibitors of FAAH -analgesic effects and reduce anxiety in animal models,
  14. 14. Cannabinoid receptors  CB1 receptors  axons and nerve termini, with little present on neuronal dendrites and the cell body.  presynaptic rather than postsynaptic side of the neuronal cleft .  CB2 - expressed on the surface of white blood cells of the immune system,
  15. 15. Cannabinoid mechanisms
  16. 16. Neurotransmission  G proteins intracellular signaling  inhibition of adenylyl cyclase  decrease in cyclic adenosine monophosphate.  Activation of potassium channels  Inhibition of N-type calcium channels  Block the release of a variety of neurotransmitters- GABA, nor epinephrine, and acetylcholine.
  17. 17.  Increase the release of brain endorphin neurotransmitters  Increase dopamine release in the nucleus accumbens  Synaptic plasticity, including LTP and long-term depression (LTD).
  18. 18.  Endocannabinoids may be the best retrograde messenger that diffuses from a postsynaptic neuron to act upon a presynaptic neuron
  19. 19.  Endocannabinoid-mediated inhibition of neurotransmission Transient and long lasting.  Transient,also termed DSI(depolarization-induced Suppression of inhibition) or DSE(depolarization- induced suppression of excitation),
  20. 20. Anxiety and Mood  Tranquillizing effect  Loss of signaling by the endocannabinoid system appears to promote anxiety-like states.  Anandamide and 2-AG were found to increase in the amygdala immediately following exposure of mice to stress
  21. 21.  Enhancing levels of endocannabinoids may represent a therapeutic target for anxiety  Novel FAAH inhibitors reduce anxiety-like behaviors  Cannabinoid interacts with 5HT1A receptors and this interaction seems to be involved in its anxiolytic-like effects
  22. 22. CB1 Antagonist-Rimonabant  Rimonabant - SR141716 or acomplia, first cb1antagonist reported.  Primary indication - Obesity  Secondary indications -improves dyslipidemia and improves glucose homeostasis.  Long term use increase suicidal ideation
  23. 23.  CB1 receptor activation enhance alcohol consumption while blocking these receptors decreases consumption  The usefulness of CB1 antagonism in smoking cessation has been investigated in the STRATUS-US trial
  24. 24. Addiction  Mice deficient in CB1 receptors - resistant to the behavioral effects of cannabinoids  Increase the release of dopamine in the nucleus accumbens,  Rats with a preference to alcohol have decreased FAAH activity
  25. 25. Psychosis  Cannabis use -worsens psychosis in schizophrenia,  Heavy use –schizophrenia  Increase the release of dopamine  Elevated levels of anandamide in CSF.  Elevated CB1 receptor levels in postmortem brain - dorsolateral prefrontal cortex and cingulate cortex
  26. 26. Feeding  Increased appetite – “munchies”  Depend on CB1 receptors present in the hypothalamus  CB1 receptor antagonist, rimonabant, appears to facilitate weight loss by blocking cannabinoid signaling.
  27. 27. Brain Injury and Pain  2-AG appears neuroprotective, reducing brain edema, infarct size, and cell death, while improving functional outcomes.  Regulate pain perception  FAAH inhibitors improved motor symptoms in a mouse model of Parkinson's disease
  28. 28.  CB1 receptor plays an important role in these effects as the analgesic effects of cannabinoid drugs are lost when CB1 antagonist rimonabant is given  Mediate stress-induced analgesia
  29. 29. Alzheimer’s disease  Analysis of postmortem brains from patients with AD- Upregulation of CB2 receptors endocannabinoid-degrading enzyme, fatty acid amide hydrolase (FAAH) in glial cells associated with senile Plaques.
  30. 30.  Direct relaxation of vascular smooth muscle by local CB1 receptors.  Conjunctiva of the eyes - “bloodshot” appearance in some cannabis users.  Relaxation of ocular arteries - treatment for glaucoma
  31. 31.  Synthetic 9 THC Dronabinol is approved in the US for treatment of nausea and vomiting associated with chemotherapy as well as an appetite stimulate in AIDS.
  32. 32. References  108-115:James Sadock,Viginia Alcott Sadock. Comprehensive text book of psychiatrty.  10.1192/bjp.178.2.116 Published 1 February 2001  Pharmacol Rev. 2006 Sep; 58(3): 389–462.  Br J Pharmacol. 2012 Apr;165(8):2485-96. doi: 10.1111/j.1476-5381.2011.01445.x.  Alexandre S. Crippa, Antonio Waldo Zuardi, Jaime E. C. Hallak:Therapeutical use of the cannabinoids in psychiatry  Kenmackie;cannabinoid receptors as therapeutic targets