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VOL. 75 (3), 389-418, 2009 CENTRAL AND PERIPHERAL ENDOGENOUS MORPHINE

analgesic activities —as well as its dangers addiction and overdose—
are common knowledge. At this time, morphine and its precursor
codeine remain the gold standard in pain relief (2, 3).

Morphine is still the most commonly used analgesic in hospitals,
mainly to relieve acute pain (especially following surgery) but
sometimes for chronic pain which is refractory to other active
compounds. After administration (orally, subcutaneous or
intravenous injection, or infusion), morphine has a half-life of about
three hours. There is no recommended maximum dose and the
amount administered can be progressively stepped up until pain
relief is obtained, as long as there are no side effects: a typical
daily dosage for chronic cancer pain in adults is 30 milligrams a
day (administered by infusion). The analgesic activity is due to the
binding of morphine to µ opiate receptors. Morphine often has
unwanted side effects, including constipation, drowsiness, nausea
and vomiting; other, less common side effects are confusion,
nightmares and, at excessive doses, respiratory depression (which
can cause apnoea and lead to death).

b) Mu (µ) opiate receptors

At the beginning of the 1970’s, the existence of specific morphine-
binding receptors was hypothesised on the basis of the drug’s
physiological effects, and soon such opiate receptors were indeed
discovered in the central nervous system (4). Most opiates (alkaloids)
and opioids (peptides) preferentially bind to Mu (µ), Delta (d) and
Kappa (?) receptors, all proteins with seven membrane-crossing
segments coupled to G proteins. Morphine and its derivative
morphine-6-glucuronide (M6G) preferentially bind a receptor
referred to as the Mu (µ) opiate receptor (MOR) or the Mu (µ) opioid
peptide receptor [MOP (5)]. Like morphine, the endogenous peptide
ligands, endomorphin-1 and endomorphin-2, have a high affinity for
µ receptors (6). The extracellular N-terminal portion of the receptor
molecule carries the ligand binding site while the intracellular
C-terminal portion is involved in signal transduction (7). These
receptors are found in both the central nervous system and the
periphery. In the brain, the highest densities of µ receptors are found

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