Long-term application of cannabinoids leads to dissociation between changes in cAMP and modulation of GABAA receptors of mouse trigeminal sensory neurons.
Neurochem Int
; 126: 74-85, 2019 06.
Article
em En
| MEDLINE
| ID: mdl-30633953
ABSTRACT
Antinociception caused by cannabinoids may have a partial peripheral origin in addition to its central site of action. In fact, we have observed that anandamide selectively and reversibly inhibits GABAA receptors of putative nociceptive neurons of mouse trigeminal sensory ganglia via CB1 receptor activation to inhibit adenylyl cyclase and decrease cAMP with downstream posttranslational alterations. Since cannabinoids are often used chronically, we studied changes in cAMP levels and GABA-mediated currents of trigeminal neurons following 24â¯h application of anandamide (0.5⯵M) or the synthetic cannabinoid WIN 55,212-2 (5⯵M). With this protocol GABA responses were similar to control despite persistent fall in cAMP levels. Inhibition by WIN 55,212-2 of GABA effects recovered after 30â¯min washout and was not associated with changes in CB1 receptor expression, indicating lack of CB1 receptor inactivation and transient loss of negative coupling between CB1 receptors and GABAA receptors. The phosphodiesterase inhibitor rolipram (100⯵M; 24â¯h) enhanced cAMP levels and GABA-mediated currents, suggesting GABAA receptors were sensitive to persistent upregulation via cAMP. While the adenylyl cyclase activator forskolin (1-20⯵M) facilitated cAMP levels and GABA currents following 30â¯min application, this action was lost after 24â¯h in line with the drug limited lifespan. The PKA inhibitor PKI 14-22 (10⯵M) increased cAMP without changing GABA currents. These data indicate that modulation of GABAA receptors by intracellular cAMP could be lost following persistent application of cannabinoids. Thus, these observations provide an insight into the waning antinociceptive effects of these compounds.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células Receptoras Sensoriais
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Canabinoides
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Gânglio Trigeminal
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Receptores de GABA-A
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AMP Cíclico
Limite:
Animals
Idioma:
En
Revista:
Neurochem Int
Ano de publicação:
2019
Tipo de documento:
Article