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The reticular formation is involved with the affective component
of pain. The aversive response and the motivational aspect of pain
are modulated via reticular activation. Similarly, the motor, autonomic,
and sensory functions that are a response to noxious stimuli are
mediated by the pathways through the reticular formation. It is
possible that the reticular formation is involved in pain behavior.64 Casey
proposes that one way in which opiates may relieve suffering without
altering an individual’s ability to recognize a stimulus
as noxious is via the reticular formation.68,69
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The hypothalamus has a role in both the autonomic nervous system
and the neuroendocrine response. The hypothalamus probably plays
a role in the response both to somatic and visceral tissue damage
and to pain.70 Thus, the emotional response and
autonomic arousal elicited by pain is likely mediated, at least
in part, by the hypothalamus. There are STT neurons that provide
nociceptive input to the many areas that are involved in producing
the multifaceted response to pain, which is familiar to clinicians.71
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The limbic system refers to a wide array of structures that are
part of the telencephalon, diencephalon, and mesencephalon. The
parts of the telencephalon that contribute to the limbic system
are the amygdala, hippocampus, nucleus accumbens, and preoptic regions.
In the diencephalon, the hypothalamus and parts of the thalamus
contribute to the limbic system. The limbic area also encompasses
the ventral tegmental area, the dorsal tegmental nucleus, and parts
of the midbrain raphe nuclei and the periaqueductal gray matter.
The interconnections between these areas and wider areas of the
cortex are complex and diverse.72 This organization
explains the allowable diversity of response to painful stimuli.
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The human cortex has two main areas that receive sensory inputs:
SI and SII. SI, on the postcentral gyrus, receives direct somatotropically
organized input from the ipsilateral ventrobasal complex of the
thalamus (the ventroposterolateral and the ventroposteromedial nuclei).
The SII area is smaller than the SI area and is located on the parietal
lobe of the cortex. The somatosensory cortex allows the discrimination
of sensation. The somatotropic organization of the somatosensory
cortex was mapped in the first half of this century by Penfield
and Rasmussen.73 The illustrated representation
of this mapping, the homunculus, is familiar to any medical student.
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The role of the sensory cortex in nociceptive processing is the
subject of renewed research and debate. Although early studies revealed
that many SI neurons respond to noxious stimuli, these responses
were putatively only localizing in nature. Further investigation
suggested that the SI neurons actually have an integrative function
whereby the intensity of a stimulus is encoded and processed.74,75 The
nitric oxide–cyclic guanosine monophosphate pathway appears
to play a role in cortical nociceptive processing.76
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The descending nociceptive modulatory system is of interest to
researchers and clinicians. Melzack and Wall proposed the existence
of a nociceptive modulating system in their seminal article in Science
in 1965.3 The gate-control hypothesis of pain proposed
that dorsal horn processing could be modified not only by stimulation
that arrived from the periphery, but also from putative descending
pathways. A few years later, Reynolds demonstrated the effect of
electrical stimulation in the periaqueductal gray matter (PAG) on
the nocifensive responses of the rat.77 It is now
widely believed that descending antinociceptive mechanisms are an
important part of an animal’s defense system.78
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The remarkable effect of PAG electrical stimulation is to diminish
or ablate the animal’s response to a noxious stimulus while
preserving the sensation of light touch.79 During
PAG electrical stimulation, the animal maintains normal motor control
and the ability to eat. Electrical stimulation of the PAG completely
inhibits the nocifensive response of an animal to a variety of noxious
stimuli, not limited to somatic stimuli, but including visceral
and tooth pulp stimulation. The analgesic response endures for a
brief time following termination of the stimulation. Electrical
stimulation of the PAG results in analgesia that is naloxone reversible,
implying an opiate-mediated response.80 Stimulation
of the PAG has been shown to provide pain relief to humans with
a variety of pain diagnoses, although it remains an experimental
therapy.81,82 There remains tremendous interest
in providing some type of pain relief to patients with neuropathic
pain. In animal models, PAG stimulation appears to provide an antinociceptive
effect.83 The result in humans, however, is more
difficult to ascertain.
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The electrical stimulation and, thus, the activation of neurons
in the PAG results in suppression of activity of dorsal horn neurons.84 Basbaum
and Fields have published extensively both together and independently
on the putative descending nociceptive modulatory systems and have
elucidated the anatomic and physiologic pathways of descending inhibition
of nociception.85,86 The PAG has connections to
the nucleus raphe magnus in the medulla, as well as to the parabrachial nucleus,
a proposed site of behavior modification.87 Subsequent
studies revealed that the function of the nucleus raphe magnus was
served by a group of nearby structures within the rostral ventromedial
medulla (RVM). The information from these rostral areas is conveyed
to the dorsal horn by way of the dorsal lateral funiculus. If any
of these structures or their connections are ablated, so is the
inhibition of nocifensive reflexes.88
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The PAG and the RVM are also involved in opiate analgesia.89 Microinjection
of morphine or of selective μ-opioid agonists into
the PAG or RVM results in potent naloxone-reversible antinociception.
Lesioning the dorsal lateral funiculus unilaterally diminishes the
opiate analgesia produced by PAG microinjection; and bilateral lesions
of the dorsal lateral funiculus ablate the opiate effect on nocifensive
reflexes. Thus, a system of descending endogenous opioid analgesia
can be elucidated, and a pathway from the PAG to the dorsal horn,
by way of the RVM and the dorsal lateral funiculus, has been demonstrated
in a variety of animal species; this pathway seems likely to exist
in humans, as well.90 The connections of the neurons
in the medulla are complex, but it appears as if serotonergic cell
projections to brainstem sites may contribute to the integration
of sensory, autonomic, and motor modulation at the brainstem level.91 There
are other loci, such as the nucleus cuneiformis, which may also
play a role in sensory and motor integration of responses to noxious
stimuli.92
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Fields and colleagues noted that the electrophysiologic responses
of neurons in the RVM to microinjection or iontophoresis of opiates
was mixed: some neurons became less active and others became more
active.93 Electrical stimulation has the effect
of activating neurons, whereas μ-opioid agonists
inhibit neuronal response. Thus, the disparate responses of neurons
to two stimuli that elicit the same analgesic response in animals
could be rectified: a heterogenous population of neurons was described.
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Certain neurons in the RVM are activated by noxious stimuli.
Called “on-cells,” these neurons fire more rapidly
during noxious stimuli, and if these cells are spontaneously firing
and a noxious stimulus is applied, the nocifensive reflex time is
shortened. μ-Opioid agonists diminish or ablate
the firing of on-cells. The second cell population stops firing before
a nocifensive reflex response occurs. These “off-cells” are
activated by opiates, and if a noxious stimulus is applied during
the spontaneous firing of an off-cell, the nocifensive reflex time
is lengthened.93
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The circuitry of the RVM involves excitatory amino acids, GABA
and opioids, as well as serotonergic and noradrenergic neurons.94 Neurotensin
microinjected into the RVM has either a facilitatory or an inhibitory
effect on the response of spinal neurons to noxious thermal stimulation, depending
on the dose of the neurotensin.95 During conditions
of analgesia, the removal of the RVM predictably lessens the analgesic
response of the animal. During conditions of hyperalgesia, the temporary
blocking of the RVM with local anesthetic actually attenuates the
hyperalgesic response.96 Thus, the RVM contains
a heterogenous population of neurons that has the potential to either ameliorate
or facilitate nociceptive transmission. This descending modulatory
system occurs in a number of species and is likely to exist in humans,
as well. And, whereas the electrophysiologic classification of neurons
in humans is likely to remain elusive, the ability to modulate hyperalgesia
and chronic pain is the goal of every pain clinician.