There are several hypotheses about how tolerance develops, including opioid receptor phosphorylation ( which would change the receptor conformation ), functional decoupling of receptors from G-proteins ( leading to receptor desensitization ), μ-opioid receptor internalization and / or receptor down-regulation ( reducing the number of available receptors for morphine to act on ), and upregulation of the cAMP pathway ( a counterregulatory mechanism to opioid effects ) ( For a review of these processes, see Koch and Hollt.

There are several hypotheses about how tolerance develops, including opioid receptor phosphorylation ( which would change the receptor conformation ), functional decoupling of receptors from G-proteins ( leading to receptor desensitization ), mu-opioid receptor internalization and / or receptor down-regulation ( reducing the number of available receptors for morphine to act on ), and upregulation of the cAMP pathway ( a counterregulatory mechanism to opioid effects ) ( For a review of these processes, see Koch and Hollt.

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