Biomedical Engineering Reference
In-Depth Information
AcO
RO
H
O
H
O
N
N
AcO
HO
Morphine R = H
Codeine R = Me
Heroin
FIGURE 19.1
Chemical structures of morphine, codeine, and heroin. 3D-structure of morphine.
prodrug since the highly potent analgesic properties can be attributed to the rapid metabolism to
6-monoacetylmorphine and morphine, combined with higher blood-brain barrier penetration due
to better lipid solubility compared to morphine.
19.1.1 O
PIOID
R
ECEPTOR
S
UBTYPES
AND
E
FFECTOR
M
ECHANISM
The idea that morphine and other opioids caused analgesia by interacting with a specii c receptor
arose around the 1950s. The observation 40 years earlier that the
N
-allyl analogue of codeine antag-
onized the respiratory action of morphine was actually an evidence of such a proposal. However,
it was i rst fully realized, when similar
N
-allyl analogue of morphine (nalorphine) was shown to
antagonize the analgesic effects of morphine.
Today, it is known that all of the opioid receptors are G-protein coupled receptors (GPCRs)
belonging to family A (Figure 19.2) that mediates its effects through Gi/Go proteins. So far, four
different opioid receptor subtypes have been cloned sharing more than 60% sequence homology.
These are termed m, k, and d receptors (corresponding to MOR, KOR, and DOR, respectively) and
an “orphan” receptor termed ORL
1
, which was the i rst orphan GPCR to be cloned.
The different effects mediated by each receptor type (m-euphoria versus k-dysphoria; m-supraspinal
analgesia versus ORL
1
-supraspinal antagonism of opioid analgesia) in the intact animal are the
result of different anatomical localizations and not due to different cellular responses. Each receptor
type has been further subdivided into m
1
/m
2
, k
1
/k
2
, and d
1
/d
2
receptors based on pharmacological
and radioligand studies. However, the origin of this subdivision is not genetically based, and it is not
known whether it arises from posttranslational modii cation, cellular localization, or interactions
with other proteins; however, it was recently shown that heterodimerization of the receptors could
be important for some of these pharmacological differences.
Morphine has the ability to both excite and inhibit single neurons. Opioid inhibition of neuronal
excitability occurs largely by the ability of opioid receptors to activate various potassium channels.
Another well-established mechanism of action is the inhibition of neurotransmitter release. The obser-
vation in 1917 that morphine inhibited the peristaltic rel ex in the guinea-pig ileum (giving rise to con-
stipation, one of the side effects of morphine) was 40 years later shown to result from the inhibition
of acetylcholine release. Also glutamate, GABA, and glycine release throughout the central nervous
system (CNS) can be inhibited by opioid receptor activation. In general, the CNS effects of opioids are
inhibitory, but certain CNS effects (such as euphoria) result from excitatory effects (Table 19.1).
19.1.2 E
NDOGENOUS
O
PIOID
R
ECEPTOR
L
IGANDS
It was proposed in the early 1970s, that the physiological role of opioid receptors was not to be target
for opium alkaloids, but that endogenous agonists might exist as mediators of the opioid system.
