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

490
SECTION II
NEUROPHARMACOLOGY
(Sorkin and Wallace, 1999). Examples of such states would be burn,
post-incision, abrasion of the skin, inflammation of the joint, and musculoskeletal
injury.
Nerve Injury
Neuroma
Peripheral nerve
degeneration...Neuroma
Spontaneous
afferent activity
Spontaneous dysesthesias
(shooting, burning pain)
Spinal
sensitization
Spinal
sensitization
Aβ afferent
fibers
Allodynia
(light touch hurts)
Figure 18–5. Mechanistic flow diagram of nerve injury–evoked
nociception.
Nerve Injury. Injury to the peripheral nerve yields complex anatomical
and biochemical changes in the nerve and spinal cord that induce
spontaneous dysesthesias (shooting, burning pain) and allodynia
(light touch hurts). This nerve injury pain state may not depend upon
the activation of small afferents, but may be initiated by low-threshold
sensory afferents (e.g., Aβ fibers). Such nerve injuries result in the
development of ectopic activity arising from neuromas formed by
nerve injury and the dorsal root ganglia of the injured axons as well
as a dororsal horn reorganization, such that low-threshold afferent
input carried by Aβ fibers evokes a pain state. This dorsal horn reorganization
reflects changes in ongoing inhibition and in the excitability
of dorsal horn projection neurons (Latremoliere and Woolf,
2009). Examples of such nerve injury-inducing events include nerve
trauma or compression (carpal tunnel syndrome), chemotherapy (as
for cancer), diabetes, and in the post-herpetic state (shingles). These
pain states are said to be neuropathic (Figure 18–5). Many clinical
pain syndromes, such as found in cancer, typically represent a combination
of these inflammatory and neuropathic mechanisms.
Although nociceptive pain usually is responsive to opioid analgesics,
neuropathic pain is typically considered to respond less well to opioid
analgesics (McQuay, 1988).
Sensory Versus Affective Dimensions. Information generated by a high
intensity peripheral stimulus initiates activity in defined pathways
that activate higher-order systems that reflect the aversive magnitude
of the stimulus. This reflects the sensory-discriminative dimension
of the pain experience (such as the ability to accurately estimate
and characterize the pain state). Painful stimuli have the certain
ability to generate strong emotional components that reflect a distinction
between pain as a specific sensation subserved by distinct
neurophysiological structures, and pain such as suffering (the original
sensation plus the reactions evoked by the sensation; the affective
motivational dimension) (Melzack and Casey, 1968). When pain
does not evoke its usual responses (anxiety, fear, panic, and suffering),
a patient’s ability to tolerate the pain may be markedly
increased, even when the capacity to perceive the sensation is relatively
unaltered. It is clear, however, that alteration of the emotional
reaction to painful stimuli is not the sole mechanism of analgesia.
Thus, intrathecal administration of opioids can produce profound
segmental analgesia without causing significant alteration of motor
or sensory function or subjective effects (Yaksh, 1988).
Mechanisms of Opioid-Induced Analgesia. The analgesic
actions of opiates after systemic delivery are
believed to represent actions in the brain, spinal cord,
and in some instances in the periphery.
Supraspinal Actions. The microinjection of opiates through chronically
placed microinjection cannulae targeted at specific brain sites
has shown that opiate agonists will, in a manner consistent with their
respective activity at a MOR, block pain behavior after delivery into
a number of highly circumscribed brain regions and that these analgesic
effects are naloxone reversible. The best characterized of these
sites is the mesencephalic periaqueductal gray (PAG) matter.
Microinjections of morphine into this region will block nociceptive
responses in every species examined from rodents to primates;
naloxone will reverse these effects.
Several mechanisms exist whereby opiates with an action
limited to the PAG may act to alter nociceptive transmission. These
are summarized in Figure 18–6. MOR agonists block release of the
inhibitory transmitter GABA from tonically active PAG systems that
regulate activity in projections to the medulla. PAG projections to
the medulla activate medullospinal release of NE and 5-HT at the
level of the spinal dorsal horn. This release can attenuate dorsal horn
excitability (Yaksh, 1997). Interestingly, this PAG organization can
also serve to increase excitability of dorsal raphe and locus coeruleus
from which ascending serotonergic and noradrenergic projections to
the limbic forebrain originate (the role of forebrain 5-HT and NE in
mediating emotional tone is discussed in Chapter 15). In humans, it
is not feasible to routinely access the site of action within the brain
where opiates may act to alter nociceptive transmission as is done in
preclinical models. However, intracerebroventricular opioids have
been employed in humans for pain relief in cancer patients.
Accordingly, it seems probable that the supraspinal site of opiate
action in the human, as in other animal models, lies close to the ventricular
lumen (Karavelis et al., 1996).
Spinal Opiate Action. A local action of opiates in the spinal cord will
selectively depress the discharge of spinal dorsal horn neurons evoked
by small (high-threshold) but not large (low-threshold) afferent nerve
fibers. Intrathecal administration of opioids in animals ranging from
mouse to human will reliably attenuate the response of the organism
to a variety of somatic and visceral stimuli that otherwise evoke pain
states. Specific opiate binding and receptor protein are limited for the
most part to the substantia gelatinosa of the superficial dorsal horn,
the region in which small, high-threshold sensory afferents show their
principal termination. A significant proportion of these opiate receptors
are associated with small peptidergic primary afferent C fibers
and the remainder are on local dorsal horn neurons. This finding is
consistent with the presence of opioid receptor protein being synthesized
in and transported from small dorsal root ganglion cells.
Confirmation of the presynaptic action is provided by the
observation that spinal opiates reduce the release of primary afferent