Intracellular Signal Transduction Mechanism
The opioid receptors belong to the G protein-coupled receptor
family. It has been demonstrated that activation of the opioid receptors leads to
activation of the pertussis toxin-sensitive G proteins (Gi
and/or Go
).
Expression of the cloned opioid receptors in cultured cells by transfection of the
cloned cDNAs has facilitated the analysis of the intracellular signal transduction
mechanisms activated by the opioid receptors ( Fig.
11-3
).[2]
Adenylate cyclase is inhibited
by opioid receptor activation, resulting in the reduction of the cellular cyclic
adenosine monophosphate (cAMP) content. Electrophysiologically, it was demonstrated
that the voltage-gated Ca2+
channel is inhibited and that the inwardly
rectifying K+
channels are activated by the opioid receptors. As a result,
neuronal excitability is reduced by activation of the opioid receptors. In contrast,
it was reported that opioids also stimulate Ca2+
influx in neuronal cultured
cells.[9]
Recently, it was shown that extracellular
signal-related kinase, a class of mitogen-activated protein kinases, is activated
by opioid receptors.[10]
Opioid-induced activation
of extracellular signal-related kinase can lead to an increase in arachidonate release
[10]
and expression of immediate early genes c-fos
and jun B.[11]
Chronic exposure of the opioid receptors to agonists induces cellular
adaptation mechanisms, which may be involved in opioid tolerance, dependence, and
withdrawal symptoms. Several investigators have shown that short-term desensitization
probably involves phosphorylation of the opioid receptors via protein kinase C.[12]
A number of other kinases also have been implicated, including protein kinase A
and β-adrenergic receptor kinase (βARK).[13]
βARK selectively phosphorylates agonist-bound receptors, thereby promoting
interactions with β-arrestins, which interfere with G protein coupling and promote
receptor internalization. Acute morphine-induced analgesia was enhanced in mice
lacking β-arrestin 2, suggesting that this protein contributes to regulation
of responsivity to opioids in vivo.[14]
Like other G protein-coupled receptors, the opioid receptors can
undergo rapid agonist-mediated internalization via a classic endocytic pathway.[15]
[16]
These processes may be induced differentially
as a function of the class
Figure 11-2
Proposed structure of the μ-opioid receptor. Red
circles indicate amino acid residues identical in the μ- and δ-opioid
receptors. TM-I to TM-VII show putative transmembrane segments composed of hydrophobic
amino acid residues.
of the ligand. For example, certain agonists, such as etorphine and enkephalins,
cause rapid internalization of the μ receptor, whereas morphine, although it decreases
adenylyl cyclase activity equally well, does not cause μ receptor internalization.
[17]
These findings suggest that different ligands
may induce different conformational
Figure 11-3
Intracellular signal transduction mechanisms linked with
the opioid receptors. Opioid agonists bind with the opioid receptors, leading to
activation of the G-protein. Activity of adenylate cyclase and the voltage-dependent
Ca2+
channels is suppressed. On the other hand, inward rectifier K+
channels and mitogen-activated protein kinase (MAPK) cascade are activated. AMP,
adenosine monophosphate; ATP, adenosine triphosphate.
changes in the receptor, leading to divergent intracellular events. Furthermore,
they may provide an explanation for differences in the efficacy and abuse potential
of various opioids.
Long-term tolerance to opioids has been thought to be associated
with superactivation of adenylyl cyclase
activity—a counter-regulation to the decrease in cAMP levels seen after acute
opioid administration.[18]
This effect is prevented
by pretreatment of cells with pertussis toxin, demonstrating involvement of G proteins
(Gi
and/or Go
).
