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

PAG OPIATE ACTION
Periaqueductal
gray
GABA-ergic
neuron
(tonically active)
Medulla
Dorsal
raphe
MOR activation
(inhibits GABA release)
Medullopetal neuron
(GABA-R)
SPINAL OPIATE
ACTION
MOR
C-fiber terminal
Ca 2+ K +
2nd order neuron
MOR
peptide transmitters such as substance P contained in small afferents
(Yaksh et al., 1980). The presynaptic action corresponds to the ability
of opiates to prevent the opening of voltage-sensitive Ca 2+ channels,
thereby preventing transmitter release. A postsynaptic action
is demonstrated by the ability of opiates to block excitation of dorsal
horn neurons directly evoked by glutamate, reflecting a direct
activation of dorsal horn projection neurons. The activation of K +
channels in these postsynaptic neurons, leading to hyperpolarization,
is consistent with a direct postsynaptic inhibition. The joint
capacity of spinal opiates to reduce the release of excitatory neurotransmitters
from C fibers and to decrease the excitability of dorsal
horn neurons is believed to account for the powerful and selective
2
PAG
1
Medulla
3
Locus
coeruleus
Spinal cord
Figure 18–6. Mechanisms of opiate action in producing analgesia.
Top left: Schematic of organization of opiate action in the periaqueductal
gray. Top right: Opiate-sensitive pathways in PAG
Mu opiate actions block the release of GABA from tonically
active systems that otherwise regulate the projections to the
medulla (1) leading to an activation of PAG outflow resulting
and activation of forebrain (2) and spinal (3) monoamine receptors
that regulate spinal cord projections (4) which provide sensory
input to higher centers and mood.
Bottom left: Schematic of primary afferent synapse with second
order dorsal horn spinal neuron, showing pre- and post-synaptic
opiate receptors coupled to Ca 2+ and K + channels, respectively.
Opiate receptor binding is highly expressed in the superficial
spinal dorsal horn (substantia gelatinosa). These receptors are
located presynaptically on the terminals of small primary afferents
(C fibers) and postsynaptially on second order neurons.
Presynaptically, activation of MOR blocks the opening of the
voltage sensitve Ca 2+ channel, which otherwise initiates transmitter
release. Postsynaptically, MOR activation enhances
opening of K + channels, leading to hyperpolarization. Thus, an
opiate agonist acting at these sites jointly serves to attenuate the
afferent-evoked excitation of the second order neuron.
4
effect of opiates on spinal nociceptive processing. In humans, there
is extensive literature indicating that a variety of opiates delivered
spinally (intrathecally or epidurally) can induce a powerful analgesia
that is reversed by low doses of systemic naloxone (Yaksh, 1997).
Peripheral Action. It has been a principal tenet of opiate action that
these agents act “centrally.” Direct application of opiates to a
peripheral nerve can, in fact, produce a local anesthetic-like action
at high concentrations, but this is not naloxone reversible and is
believed to reflect a “nonspecific” action. Moreover, in studies
examining normal animals, it can be demonstrated that the analgesic
actions are limited if the agent does not readily penetrate the
brain. Alternately, studies employing the direct injection of these
agents into peripheral sites have demonstrated that under conditions
of inflammation, where there is an increased terminal sensitivity
leading to an exaggerated pain response (e.g., hyperalgesia),
the local action of opiates can exert a normalizing effect upon the
exaggerated thresholds. This has been demonstrated for the
response to mechanical stimulation applied to inflamed paw or
inflamed knee joints. In the absence of inflammation, there is no
local peripheral effect. This action is believed to be mediated by
opiate receptors on the peripheral terminals of small primary afferents.
Local opiates in the knee joint and in the skin can reduce the
firing of spontaneously active afferents observed when these tissues
are inflamed. Whether the effects are uniquely on the afferent
terminal, whether the opiate acts upon inflammatory cells that
release products that sensitize the nerve terminal, or both, is not
known (Stein and Lang, 2009).
Mood Alterations and Rewarding Properties. The
mechanisms by which opioids produce euphoria, tranquility,
and other alterations of mood (including
rewarding properties) are complex and not entirely
clear. Neural systems thought to mediate opioid reinforcement
overlap with, but are distinct from, those
involved in physical dependence and analgesia (Koob et
al., 1988). Behavioral and pharmacological data point
to a pivotal role of the mesocorticolimbic (MCL)
dopamine system, a basal forebrain circuit long implicated
in reward and motivation (Figure 18–7).
The mesolimbic dopamine system originates in the ventral
segmental area (VTA) and projects to the nucleus accumbens (NAc)
in the forebrain. Dopamine and glutamate projections from the VTA
and prefrontal cortex (PFC), respectively, synapse on NAc
GABAergic neurons. These cells project to the ventral pallidum
(VP). In the NAc, ionotropic glutamate receptors activate, while
dopamine D 2
-like receptors inhibit GABAergic neurons. In general,
interventions that suppress the NAc-VP GABA pathway leading to
increased dopamine release are considered to be positively rewarding,
supporting, for example, self-administration. Thus, dopamine
delivered directly into the NAc, mimicking increased extracellular
release, is powerfully reinforcing. Opiates increase DA release in
the NAc, and catheterized animals will activate administration of
opiates directly into their VTA and into the NAc, emphasizing the
importance of that system in opiate reward. In the NAc, MORs are
present postsynaptically on GABAergic neurons. The reinforcing
effects of opiates in the VTA are thought to be mediated through
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CHAPTER 18
OPIOIDS, ANALGESIA, AND PAIN MANAGEMENT