Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

INTRODUCTION
standard nomenclature, also known as ORL-1) that
interacts with some opioid-like peptides orphanin-FQ
or nociceptin but not the classic opioid drugs. The
potential role of this receptor in pain control is still
being investigated.
Other types and subtypes of opioid receptor have
been suggested on the basis of indirect pharmacological
evidence but their existence has either been ruled out or
they have not yet been clearly established. The sigma
(σ) receptor is no longer considered to be an opioid
receptor.
The epsilon (ε) receptor is not a distinct opioid receptor,
being best explained by the presence of a very low
density of µ receptors in some tissues. The suggestion
that a subtype of µ-receptor is the target of the
major active metabolite of morphine, morphine-6-
glucuronide, has little or no experimental support.
Further receptor subclassifications such as µ1 and µ2,
δ1 and δ2 and κ1 and κ2 are controversial. It remains
possible but not established that some subtypes arise
from alternatively spliced mRNA products of transcripts
of the three major receptors, or from hetero-oligomerization
among the three major receptor types. The κ3
subtype is no longer accepted.
Effector mechanisms
Opioid drugs mimic the actions of endogenous opioids
(endorphins), which are peptides produced in the
nervous and endocrine systems that stimulate opioid
receptors. A number of opioid peptides ranging in size
from five to over 30 amino acids are synthesized from
the three large precursors: pro-opioimelanocortin, proenkephalin
and prodynorphin. Endogenous opioid
systems appear to usually have only weak tonic activity
but become highly active under certain environmental
conditions, e.g. during extreme stress and pain. The
analgesic activity of some opioid drugs (e.g. tramadol)
is due to interaction with opioid receptors as well as
other neurotransmitter systems.
Different opioid drugs bind to distinct opioid receptors
with varying degrees of affinity and have differing
durations of action, which result in different pharmacological
profiles. To complicate matters, a given opioid
drug may act as an agonist, a partial agonist or an
antagonist at each type of receptor (Fig. 14.1). Selection
of an opioid for a particular use depends on these
properties as well as its absorption, distribution
and metabolism.
All the cloned opioid receptor types belong to the
Gi/Go-coupled superfamily of receptors. Under normal
circumstances opioid receptors do not couple directly
with Gs or Gq and none of the cloned receptors forms
a ligand-gated ion channel. All three classic receptor
types (µ, δ and κ) and the NOP-receptor couple through
Gi/Go proteins generally share common effector mechanisms,
e.g. they can all activate inwardly rectifying
potassium conductance and inhibit voltage-operated
calcium conductances in cell membranes to produce
inhibition of excitability. However, different responses
can be evoked in different cell types in response to activation
of different opioid receptors. These are likely
to reflect changes in the expression of G proteins and
effector systems between cell types rather than any
inherent differences in the properties of the receptors
themselves.
Opioid receptor activation produces a wide array of
cellular responses, the net result of which depends upon
the location of each receptor type in the nervous system
and on the specific biochemical cascades activated in
different types of cell. For example, µ-opioid receptors
are located throughout neural systems responsible for
pain sensation, from the spinal cord to the brain. The
inhibition of pain transmission produced by µ-opioid
agonists is highly selective and other sensory modalities
are not disrupted. µ-Receptors also occur on nerve cells
responsible for generating respiratory rhythms in the
brainstem and thus depress respiration when stimulated.
Receptor selectivity, distribution and pharmacological
responses produced by opioid agonists are summarized
in Table 14.1.
All opioid receptors appear to function primarily by
exerting inhibitory modulation of synaptic transmission
in both the CNS and various peripheral nerve cells,
including the myenteric plexus. Receptors are often
found on presynaptic nerve terminals, where their action
results in decreased release of neurotransmitters, or on
nerve cell bodies, where they inhibit the generation of
action potentials. In some parts of the nervous system
opioid receptors inhibit excitatory neurotransmission
and in others release of inhibitory neurotransmitters is
impaired, leading to disinhibition or a net excitatory
effect.
Known drug interactions with opioid receptors
Some opioids act with high efficacy and potency at one
receptor type and with much lower potency and lower
efficacy at other receptors; these are called full agonists,
e.g. morphine at µ-receptors. Some opioids are partial
agonists at one receptor type, e.g. buprenorphine is a
partial µ-receptor agonist with little activity at other
types. Others are mixed agonist-antagonists, having
agonist actions at one receptor type and antagonist
activity at others (e.g. nalbuphine is a µ-antagonist as
well as a κ-agonist).
Endogenous opioid peptides display some selectivity
for different receptor types. Enkephalins and β-
endorphin interact selectively with both µ- and δ-
receptors. Dynorphins are selective for κ-receptors and
endomorphins are selective for µ-receptors; however,
the existence of endomorphins will remain tentative
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