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1. Morphine, used long‐term for the treatment of pain, results in drug tolerance. The therapeutic benefits, as well as side effects, of morphine are mediated predominantly via activation of μ‐opioid receptors. Although the underlying mechanisms for opioid tolerance remains unclear, early adaptive processes, such as acute receptor desensitization and receptor downregulation, have been suggested to be crucial to the development of opioid tolerance.

2. Other neuroadaptations resulting from chronic opioid use include upregulation of the cAMP pathway, an increase in the cAMP response element‐binding protein and Fos‐related antigens. However, the connection between upregulation of these cellular elements and the mechanism behind the behavioural phenomenon remains unclear.

3. Acute receptor desensitization is thought to occur via uncoupling of the receptor and G‐protein, which is followed by …