DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Proorphanin
485
Orphanin
Prodynorphin
Proenkephalin
POMC
KEY
Leu-Enkephalin
Met-Enkephalin
respective agonists and also in the agonist-induced intracellular signaling
(Gupta et al., 2006).
Alternative Splicing of Receptor RNA
Alternative splicing of receptor heteronuclear RNA (e.g., exon skipping
and intron retention) is thought to play an important role in
producing in vivo diversity within many members of the GPCR
superfamily (Chapter 3). Splice variants exist within each of the
three opioid receptor families, and this alternative splicing of receptor
transcripts may be crucial for the diversity of opioid receptors. As
an example, the human Oprm gene has at least two promoters, multiple
exons, with many exons generating at least 11 splice variants
that encode multiple morphine-binding isoforms, varying largely
at their carboxy (intracellular) terminus. Given the functional importance
of the intracellular components of the GPCRs, it is not surprising
that significant differences exist for the receptor isoforms in terms of
agonist-induced G protein activation and receptor internalization.
Importantly, these splice variants have been found expressed in vivo
(Pan, 2005).
Receptor Subtype Agonists/Antagonists
Studies on the presence and function of these receptors have
depended upon the convergence between agonist/antagonist
structure-activity studies and a variety of functional assays in biological
and cloned receptor systems. Highly selective agonists have
α-Neoendorphin
Dynorphin A
Peptide F
OctaPeptide
Dynorphin B
HeptaPeptide
ACTH
γ-LPH
Figure 18–1. Peptide precursors. (Reproduced with permission from Akil et al, 1998. Copyright © Elsevier.)
β-MSH
β-LPH
β-Endorphin
been developed that show specific affinity for the respective binding
site and G-protein coupled reporter activation in cloned expression
systems (e.g., DAMGO for MOR, DPDPE for DOR, and
U-50,488, and U-69,593 for KOR) (Table 18–1). The study of the
biological functions of opioid receptors in vivo has been aided by
synthesis of selective antagonists. Among the most commonly used
antagonists are cyclic analogs of somatostatin such as CTOP as a
MOR antagonist, a derivative of naloxone called naltrindole as a
DOR-receptor antagonist, and a bivalent derivative of naltrexone
called nor-binaltorphimine (nor-BNI) as a KOR antagonist. These
tools have made possible the characterization of the distribution of
binding which, in conjunction with immunohistochemistry using
antibodies derived from cloned receptors, has served to define the
anatomical distribution of the receptors and the roles of the respective
receptors in biological functions. Positron emission tomography
(PET) has been used to characterize in vivo binding in brain with
selective isotopically labeled ligands (Henriksen and Willoch, 2008).
In vivo delivery of selective antagonists and agonists into specific
brain regions has established the receptor types and anatomical distribution
involved in mediating various opioid effects (see below).
Receptor Structure
Each receptor consists of an extracellular N-terminus, seven transmembrane
helices, three extra- and intracellular loops, and an intracellular
C-terminus characteristic of the GPCRs. The opioid receptors
CHAPTER 18
OPIOIDS, ANALGESIA, AND PAIN MANAGEMENT