Cannabidiol-induced panicolytic-like effects and fear-induced antinociception impairment: the role of the CB1 receptor in the ventromedial hypothalamus

Aimone LD, Bauer CA, Gebhart GF (1988) Brain-stem relays mediating stimulation-produced antinociception from the lateral hypothalamus in the rat. J Neurosci 8:2652–2663 Almada RC, Coimbra NC (2015) Recruitment of striatonigral disinhibitory and nigrotectal inhibitory GABAergic pathways during the organization of defensive behavior by mice in a dangerous environment with the venomous snake Bothrops alternatus (Reptilia Viperidae). Synapse 69:299–313 Almada RC, Roncon CM, Elias-Filho DH, Coimbra NC (2015) Endocannabinoid signaling mechanisms in the substantia nigra pars reticulata modulate GABAergic nigrotectal pathways in mice threatened by urutu-cruzeiro venomous pit viper. Neuroscience 303:503–514 Azad SC, Eder M, Marsicano G, Lutz B, Zieglgänsberger W, Rammes G (2003) Activation of the cannabinoid receptor type 1 decreases glutamatergic and GABAergic synaptic transmission in the lateral amygdala of the mouse. Learn Mem 10:116–128 Azad SC, Kurz J, Marsicano G, Lutz B, Zieglgänsberger W, Rammes G (2008) Activation of CB1 specifically located on GABAergic interneurons inhibits LTD in the lateral amygdala. Learn Mem 15:143–152 Battista N, Di Tommaso M, Bari M, Maccarrone M (2012) The endocannabinoid system: an overview. Front Behav Neurosci 6:9 Biagioni AF, Freitas RL, de Silva JA, de Oliveira RC, de Oliveira R, de Alves VM, Coimbra NC (2013) Serotonergic neural links from the dorsal raphe nucleus modulate defensive behaviours organised by the dorsomedial hypothalamus and the elaboration of fear-induced antinociception via locus coeruleus pathways. Neuropharmacology 67:379–394 Biagioni AF, dos Anjos-Garcia T, Ullah F, Fisher IR, Falconi-Sobrinho LL, de Freitas RL, Felippotti TT, Coimbra NC (2016a) Neuroethological validation of an experimental apparatus to evaluate oriented and non-oriented escape behaviours: comparison between the polygonal arena with a burrow and the circular enclosure of an open-field test. Behav Brain Res 298(Pt B):65–77 Biagioni AF, Oliveira RC, de Oliveira R, da Silva JA, dos Anjos-Garcia T, Roncon CM, Corrado AP, Zangrossi H Jr (2016b) 5-Hydroxytryptamine 1A receptors in the dorsomedial hypothalamus connected to dorsal raphe nucleus inputs modulate defensive behaviours and mediate innate fear-induced antinociception. Eur Neuropsychopharmacol 26:532–545 Bisogno T, Hanus L, de Petrocellis L, Tchjlibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134:845–852 Blessing EM, Steenkamp MM, Manzanares J, Marmar CR (2015) Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics 12:825–836 Bolles RC, Fanselow MS (1980) A perceptual-defensive-recuperative model of fear and pain. Behav Brain Sci 3:291 Bushnell MC, Čeko M, Low LA (2013) Cognitive and emotional control of pain and its disruption in chronic pain. Nat Rev Neurosci 14:502–511 Butler RK, Finn DP (2009) Stress-induced analgesia. Prog Neurobiol 88:184–202 Calvo F, Almada RC, dos Anjos-Garcia T, Falconi-Sobrinho LL, Paschoalin-Maurin T, Bazaglia-de-Sousa G, Lobão-Soares B, Coimbra NC (2019a) Panicolytic-like effect of μ1-opioid receptor blockade into the inferior colliculus of rats threatened by Crotalus durissus terrificus pit vipers. J Psychoharmacol 33(5):577–588 Calvo F, Lobão-Soares B, de Freitas RL, Paschoalin-Maurin T, dos Anjos-Garcia T, Medeiros P, da Silva JA, Lovick TA, Coimbra NC (2019b) The endogenous opioid system modulates defensive behavior evoked by Crotalus durissus terrificus: Panicolytic-like effect of intracollicular non-selective opioid receptors blockade. J Psychopharmacol 33(1):51–61 Canteras NS (2002) The medial hypothalamic defensive system: hodological organization and functional implications. Pharmacol Biochem Behav 71:481–491 Campos AC, Guimarães FS (2008) Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology 199:223–230 Casarotto PC, Terzian ALB, Aguiar DC, Zangrossi H, Guimarães FS, Wotjak CT, Moreira FA (2012) Opposing roles for cannabinoid receptor type-1 (CB1) and transient receptor potential vanilloid type-1 channel (TRPV1) on the modulation of panic-like responses in rats. Neuropsychopharmacology 37:478–486 Coimbra NC, Calvo F, Almada RC, Freitas RL, Paschoalin-Maurin T, dos Anjos-Garcia T, Elias-Filho DH, Ubiali WA, Lobão-Soares B, Tracey I (2017a) Opioid neurotransmission modulates defensive behavior and fear-induced antinociception in dangerous environments. Neuroscience 354:178–195 Coimbra NC, de Oliveira R, Freitas RL, Ribeiro SJ, Borelli KG, Pacagnella RC, Moreira JE, da Silva LA, Mello LL, Lunardi LO, Brandão ML (2006) Neuroanatomical approaches of the tectum-reticular pathways and immunohistochemical evidence for serotonin-positive perikarya on neuronal substrates of the superior colliculus and periaqueductal gray matter involved in the elaboration of the defensive behavior and fear-induced analgesia. Exp Neurol 197:93–112 Coimbra NC, Mendes-Gomes J, da Silva JA, dos Anjos-Garcia T, Ullah F, Almada R.C (2017b) Ethological and morphological perspectives for the investigation of panicolytic-like effect of cannabidiol. In: The handbook of cannabis and related pathologies: biology, diagnosis, treatment, and pharmacology (Victor R. Preedy, ed.). Elsevier Science Publishers Amsterdam pp. e140-e149 Coimbra NC, Paschoalin-Maurin T, Bassi GS, Kanashiro A, Biagioni AF, Felippotti TT, Elias-Filho DH, Mendes-Gomes J, Cysne-Coimbra JP, Almada RC, Lobão-Soares B (2017c) Critical neuropsychobiological analysis of panic attack- and anticipatory anxiety-like behaviors in rodents confronted with snakes in polygonal arenas and complex labyrinths: a comparison to the elevated plus- and T-maze behavioral tests. Braz J Psychiatr 39:72–83 Connell K, Bolton N, Olsen D, Piomelli D, Hohmann AG (2006) Role of the basolateral nucleus of the amygdala in endocannabinoid-mediated stress-induced analgesia. Neurosci Lett 397:180–184 da Silva JA, Biagioni AF, Almada RC, de Souza Crippa JA, Hallak JEC, Zuardi AW, Coimbra NC (2015) Dissociation between the panicolytic effect of cannabidiol microinjected into the substantia nigra, pars reticulata, and fear-induced antinociception elicited by bicuculline administration in deep layers of the superior colliculus: the role of CB1-cannabinoid receptor in the ventral mesencephalon. Eur J Pharmacol 758:153–163 da Silva Soares R Jr, Falconi-Sobrinho LL, dos Anjos-Garcia T, Coimbra NC (2019) 5-Hydroxytryptamine 2A receptors of the dorsal raphe nucleus modulate panic-like behaviours and mediate fear-induced antinociception elicited by neuronal activation in the central nucleus of the inferior colliculus. Behav Brain Res 357-358:71–81 de Gregorio D, McLaughlin RJ, Posa L, Ochoa-Sanchez R, EnnsJ L-CM, Aboud M, Maione S, Comai S, Gobbi G (2019) Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. Pain 160:136–150 dos Anjos-Garcia T, Coimbra NC (2019) Opposing roles of dorsomedial hypothalamic CB1 and TRPV1 receptors in anandamide signaling during the panic-like response elicited in mice by Brazilian rainbow Boidae snakes. 236, 1863-1874 dos Anjos-Garcia T, Ullah F, Falconi-Sobrinho LL, Coimbra NC (2017) CB1 cannabinoid receptor-mediated anandamide signalling reduces the defensive behaviour evoked through GABAA receptor blockade in the dorsomedial division of the ventromedial hypothalamus. Neuropharmacology 113:156–166 Falconi-Sobrinho LL, dos Anjos-Garcia T, Elias-Filho DH, Coimbra NC (2017a) Unravelling cortico-hypothalamic pathways regulating unconditioned fear-induced antinociception and defensive behaviours. Neuropharmacology 113:367–385 Falconi-Sobrinho LL, dos Anjos-Garcia T, de Oliveira R, Coimbra NC (2017b) Decrease in NMDA receptor-signalling activity in the anterior cingulate cortex diminishes defensive behaviour and unconditioned fear-induced antinociception elicited by GABAergic tonic inhibition impairment in the posterior hypothalamus. Eur Neuropsychopharmacol 27:1120–1131 Falconi-Sobrinho LL, Coimbra NC (2018) The nitric oxide donor SIN-1-produced panic-like behaviour and fear-induced antinociception are modulated by NMDA receptors in the anterior hypothalamus. J Psychopharmacol 32:711–722 Freitas RL, Uribe-Mariño A, Castiblanco-Urbina MA, Elias-Filho DH, Coimbra NC (2009) GABAA receptor blockade in dorsomedial and ventromedial nuclei of the hypothalamus evokes panic-like elaborated defensive behaviour followed by innate fear-induced antinociception. Brain Res 1305:118–131 Glass M, Dragunow M, Faull RL (1997) Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain. Neuroscience 77:299–318 Gomes FV, Resstel LBM, Guimarães FS (2011) The anxiolytic-like effects of cannabidiol injected into the bed nucleus of the stria terminalis are mediated by 5-HT1A receptors. Psychopharmacology 213:465–473 Gonçalves TCT, Londe AK, Albano RIP, de Araújo Júnior AT, de Aguiar AM, Biagioni AF, Vasconcellos THF, dos Reis Ferreira CM, Teixeira DG, de Souza Crippa JA, Vieira D, Coimbra NC (2014) Cannabidiol and endogenous opioid peptide-mediated mechanisms modulate antinociception induced by transcutaneous electrostimulation of the peripheral nervous system. J Neurol Sci 347:82–89 Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker FM, Holmes FV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D (2005) An endocannabinoid mechanism for stress-induced analgesia. Nature 435:1108–1112 Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, Russo E, Whalley BJ, Di Marzo V, Stephens GJ (2014) Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci 5:1131–1141 Johnson PL, Shekhar A (2006) Panic-prone state induced in rats with GABA dysfunction in the dorsomedial hypothalamus is mediated by NMDA receptors. J Neurosci 26:7093–7104 López-Moreno JA, González-Cuevas G, Moreno G, Navarro M (2008) The pharmacology of the endocannabinoid system: functional and structural interactions with other neurotransmitter systems and their repercussions in behavioral addiction. Addict Biol 13:160–187 Mackie K (2008) Cannabinoid receptors: where they are and what they do. J Neuroendocrinol 20:10–14 Marinho ALZ, Vila-Verde C, Fogaça MV, Guimarães FS (2015) Effects of intra-infralimbic prefrontal cortex injections of cannabidiol in the modulation of emotional behaviors in rats: contribution of 5HT1A receptors and stressful experiences. Behav Brain Res 286:49–56 Mechoulam R, Peters M, Murillo-Rodrigue E, Hanuš LO (2007) Cannabidiol – recent advances. Chem Biodivers 4:1678–1692 Maione S, Piscitelli F, Gatta L, Vita D, De Petrocellis L, Palazzo E, de Novellis V, Di Marzo V (2011) Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action. Br J Pharmacol 162:584–596 McPartland JM, Duncan M, Di Marzo V, Pertwee RG (2015) Are cannabidiol and Δ(9)-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol 172:737–753 Misner DL, Sullivan JM (1999) Mechanism of cannabinoid effects on long-term potentiation and depression in hippocampal CA1 neurons. J Neurosci 19:6795–6805 Millan MJ (2002) Descending control of pain. Prog Neurobiol 66:355–474 Myers RD (1966) Injection of solutions into cerebral tissue: relation between volume and diffusion. Physiol Behav 1:171–174 Neelakantan H, Tallarida RJ, Reichenbach ZW, Tuma RF, Ward SJ, Walker EA (2015) Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice. Behav Pharmacol 26:304–314 Palazzo E, de Novellis V, Marabese I, Cuomo D, Rossi F, Berrino L, Rossi F, Maione S (2002) Interaction between vanilloid and glutamate receptors in the central modulation of nociception. Eur J Pharmacol 439:69–75 Paschoalin-Maurin T, dos Anjos-Garcia T, Falconi-Sobrinho LL, de Freitas RL, Coimbra JPC, Laure CJ, Coimbra NC (2018) The rodent-versus-wild snake paradigm as a model for studying anxiety- and panic-like behaviors: face, construct and predictive validities. Neuroscience 369:336–349 Paxinos G, Watson C (2007) The rat brain in stereotaxic coordinates, 6th edn. Academic Press, San Diego Roche M, O’Connor E, Diskin C, Finn DP (2007) The effect of CB(1) receptor antagonism in the right basolateral amygdala on conditioned fear and associated analgesia in rats. Eur J Neurosci 26:2643–2653 Rodríguez-Muñoz M, Onetti Y1, Cortés-Montero E, Garzón J, Sánchez-Blázquez P (2018) Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor. Mol Brain 17:11–51 Routtenberg A (1972) Memory as input-output reciprocity: an integrative neurobiological theory. Ann N Y Acad Sci 193:159–174 Russo EB, Burnett A, Hall B, Parker KK (2005) Agonist properties of cannabidiol at 5-HT1A receptors. Neurochem Res 30:1037–1043 Schier ARM, Ribeiro NP, Silva AC, Hallak JEC, Crippa JAS, Nardi AE, Zuardi AW (2012) Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug. Rev Bras Psiquiatr 34:S104–S117 Shekhar A, DiMicco JA (1987) Defense reaction elicited by injection of GABA antagonists and synthesis inhibitors into the posterior hypothalamus in rats. Neuropharmacology 26:407–417 Soares VP, Campos AC, Bortoli VC, Zangrossi H Jr, Guimarães FS, Zuardi AW (2010) Intra-dorsal periaqueductal gray administration of cannabidiol blocks panic-like response by activating 5-HT1A receptors. Behav Brain Res 213:225–229 Spiacci A Jr, de Oliveira ST, da Silva GSF, Glass ML, Schenberg LC, Garcia-Cairasco N, Zangrossi H Jr (2015) Serotonin in the dorsal periaqueductal gray inhibits panic-like defensive behaviors in rats exposed to acute hypoxia. Neuroscience 307:191–198 Spiacci A Jr, Vilela-Costa HH, Sant'Ana AB, Fernandes GG, Frias AT, da Silva GSF, Antunes-Rodrigues J, Zangrossi H Jr (2018) Panic-like escape response elicited in mice by exposure to CO2, but not hypoxia. Prog Neuro-Psychopharmacol Biol Psychiatry 81:178–186 Takahashi KA, Castillo PE (2006) The CB1 cannabinoid receptor mediates glutamatergic synaptic suppression in the hippocampus. Neuroscience 139:795–802 Twardowschy A, Castiblanco-Urbina MA, Uribe-Mariño A, Biagioni AF, Salgado-Rohner CJ, de Souza-Crippa JA, Coimbra NC (2013) The role of 5-HT1A receptors in the anti-aversive effects of cannabidiol on panic attack-like behaviors evoked in the presence of the wild snake Epicrates cenchria crassus (Reptilia, Boidae). J Psychopharmacol 27:1149–1159 Ullah F, dos Anjos-Garcia T, Mendes-Gomes J, Elias-Filho DH, Falconi-Sobrinho LL, de Freitas RL, Khan AU, de Oliveira R, Coimbra NC (2017) Connexions between the dorsomedial division of the ventromedial hypothalamus and the dorsal periaqueductal grey matter are critical in the elaboration of hypothalamically mediated panic-like behaviour. Behav Brain Res 319:135–147 Ullah F, dos Anjos-Garcia T, dos Santos IR, Biagioni AF, Coimbra NC (2015) Relevance of dorsomedial hypothalamus, dorsomedial division of the ventromedial hypothalamus and the dorsal periaqueductal gray matter in the organization of freezing or oriented and non-oriented escape emotional behaviors. Behav Brain Res 293:143–152 Uribe-Mariño A, Francisco A, Castiblanco-Urbina MA, Twardowschy A, Salgado-Rohner CJ, Crippa JAS, Hallak JEC, Zuardi AW, Coimbra NC (2012) Anti-aversive effects of cannabidiol on innate fear-induced behaviors evoked by an ethological model of panic attacks based on a prey vs the wild snake Epicrates cenchria crassus confrontation paradigm. Neuropsychopharmacology 37:412–421 Viana TG, Hott SC, Resstel LB, Aguiar DC, Moreira FA (2015) Anti-aversive role of the endocannabinoid system in the periaqueductal gray stimulation model of panic attacks in rats. Psychopharmacology 232:1545–1553 Wilent WB, Oh MY, Buetefisch CM, Bailes JE, Cantella D, Angle C, Whiting DM (2010) Induction of panic attack by stimulation of the ventromedial hypothalamus. J Neurosurg 112:1295–1298 Wolkers CPB, Barbosa Junior A, Menescal-de-Oliveira L, Hoffmann A (2015) Acute administration of a cannabinoid CB1 receptor antagonist impairs stress-induced antinociception in fish. Physiol Behav 142:37–41 Zou S, Somvanshi RK, Paik S, Kumar U (2015) Colocalization of cannabinoid receptor 1 with somatostatin and neuronal nitric oxide synthase in rat brain hypothalamus. J Mol Neurosci 55:480–491