Neuroprotective Effect of Naloxone in Inflammation-Mediated Dopaminergic Neurodegeneration - Drugs of Abuse: Neurological Reviews and Protocols - page 42

classes of classic opioid receptors: (9 , 10) . They are all G-protein-

linked receptors with seven transmembrane domains and multiple potential
phosphorylation sites in the terminal sequences. Pharmacological studies have
further suggested the existence of subgroups within the three types of opioid
receptors. However, molecular cloning has yet to confi rm this. Nevertheless,
various endogenous opioid peptides exhibit differential affi nity toward the three
types of opioid receptors. For example, methionine-enkephalin and leucine-
enkephalin preferentially bind

, , and µ

-opioid receptor and dynorphins show some

selectivity toward -opioid receptor, while -endorphin has a slightly higher

-opioid receptor than the other two types of receptors (9 , 11) .
The dissociation constants of endogenously opioid peptides for opioid receptors
are in the range of 10 -9 M . Naturally occurring opiates such as morphine elicit
physiologic responses by mimicking endogenous opioid peptides in binding
to opioid receptors.

affi nity for the µ

2. Naloxone
Naloxone is a synthetic and nonselective antagonist against all three classic
opioid receptors. Structurally, it closely resembles the naturally occurring
opiate morphine ( Fig. 1 ). As with morphine, the binding of naloxone to opioid
receptors is stereospecifi c, such that (-)-naloxone (also called L -naloxone for
the levorotatory confi guration of the asymmetric carbon) binds the µ -opioid

10 -9 M ).
The affi nity of (+)-naloxone (also called R -naloxone), however, is three to four
orders of magnitude less than that for (-)-naloxone (12 , 13) . Therefore, ever
since their synthesis and characterization, the naloxone enantiomers have been
one of the most powerful tools in the investigation of the involvement of opioid
receptors in various systems.
Over the last 30 yr, the ever increasing realization of the involvement of
opioid systems in a wide variety of physiological as well as pathophysiological
conditions, beyond the initially described roles in the nociceptive/analgesic
systems, has certainly prompted an intensive screening of opioid receptor
antagonists for potential therapeutic purposes. Because of its potent antagonistic
activity, ease of crossing the blood-brain barrier, and relatively low systemic
toxicity, (-)-naloxone has been tested for benefi cial effects in a variety of
experimental disease models. Mechanistically, the effi cacy in the experimental
treatment of conditions such as opiate dependence is certainly related to its
activity as an opioid receptor antagonist (14) , whereas in the treatment of eating
disorders (15) and alcoholism (16) , the opioid system most likely plays a role.
However, the underlying mechanisms of action for the experimental treat-
ment of traumatic brain and spinal cord injuries (17) , myocardial and cerebral
stroke (18-22) , and sepsis (23) are far from clear and are definitely not

receptor with the same dissociation constant as that for morphine (~2 ×