Spinal Cord Plasticity and Pain

SUMMARY

Clinically relevant forms of pain cannot be fully understood without appreciating the various forms of plasticity that develop in the spinal dorsal horn after injury or with disease. All major components of the spinal cord nociceptive network are subject to potential short- and long-term plasticity. This applies in particular to the synaptic contacts between nociceptive nerve fibers and spinal dorsal horn neurons. Synaptic strength is not static but may be enhanced or depressed for long periods. For example, inflammation and neuropathy may induce long-term potentiation at the first synaptic relay between nociceptive nerve fibers and neurons in the superficial spinal dorsal horn. Long-term potentiation is a cellular model for pain amplification. Nociceptive nerve fibers, spinal interneurons, and projection neurons communicate with each other and with spinal microglia and astrocytes. Transfer of information in spinal nociceptive circuits is under powerful segmental and supraspinal control, both inhibitory and facilitatory. Proper modulation is essential for normal nociception but may change quickly and significantly under conditions of peripheral inflammation or nerve injury. Long-term potentiation and disinhibition are two forms of neural plasticity that contribute to hyperalgesia. Disinhibition in addition causes breakdown of somatotopic and modality borders, which leads to spreading pain and allodynia. The list of relevant substances released into the spinal dorsal horn by neurons and glial cells in the course of neuropathy, trauma, or inflammation is growing rapidly, as is the ensemble of participating receptors and signaling pathways. We are now beginning to understand that depending on the primary cause of pain, the spinal nociceptive network may enter distinct modes of operation. This then leads to different forms of pain amplification, pain generation, and pain referral. The various forms of spinal dorsal horn plasticity are currently unfolding as summarized in this chapter. In-depth understanding of plasticity in spinal nociceptive pathways is a key requirement for targeting chronic pain states.

Some Useful Definitions

Nociception versus Pain

Nociception includes all forms of information processing triggered by noxious stimuli (i.e., stimuli that are damaging to normal tissues). In awake animals or human subjects, nociception may lead to withdrawal or vegetative responses and/or to the sensation of pain. Pain as defined by the International Association for the Study of Pain (IASP) is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.” Although pain is always a subjective sensation, nociception can be measured in terms of objective parameters.

Nociceptive Neurons

Defined by their excitatory input, nociceptive neurons include all neurons that are excited by noxious stimuli. This classification is irrespective of the function or functions that the neurons might serve. Nociceptive-specific neurons are excited by nociceptive afferents only. Some spinal nociceptive neurons, however, receive convergent input from high- and low-threshold sensory fibers (wide–dynamic range neurons), some have projections to the brain, whereas other nociceptive neurons are inhibitory. Still others are excitatory interneurons or motoneurons that trigger withdrawal responses. Thus, excitation of a given type of nociceptive neuron may be irrelevant for the sensation of pain (e.g., nociceptive flexor motoneurons) or may dampen pain intensity (e.g., some inhibitory interneurons), whereas activity in other nociceptive neurons (e.g., spinal dorsal horn projection neurons) may lead to the sensation of pain (see also the next definitions).

Antinociceptive Neurons

Antinociceptive neurons are defined by their output and inhibit nociceptive neurons or nociceptive responses. Some antinociceptive neurons are excited by noxious stimuli and thus constitute a subgroup of nociceptive neurons.

Principal Pain Neurons

Defined by their function, principal pain neurons trigger the sensation of pain when activated. At present, no principal pain neurons have been identified with certainty. It appears, however, that in the peripheral nervous system, some (but not all) nociceptive nerve fibers are principal pain neurons. Excitation of a subgroup of primary afferent nociceptive nerve fibers is sufficient to trigger pain sensation in human subjects ( ). This supports the specificity theory of pain ( ), which states that pain is a “specific sensation, with its own sensory apparatus independent of touch and other senses.” It is possible that principal pain neurons also exist in the central nervous system (CNS). Good candidates are nociceptive-specific spinal dorsal horn neurons ( ) with a projection to the thalamus, the midbrain periaqueductal gray, and/or the parabrachial area. Some of these ascending nociceptive pathways could constitute “labeled lines” for pain ( ). An alternative hypothesis states that the activity pattern of an ensemble of CNS neurons determines the type of sensation that is experienced by an individual. This is proposed by the pattern theory of pain ( ). See also discussions by , , and .

Pro-nociceptive Helper Cells

Activation of pro-nociceptive helper cells does not directly mediate pain sensation but rather facilitates nociception. Pro-nociceptive helper cells may be excitatory interneurons, descending tract neurons, or non-neuronal cells such as glial cells or blood cells that facilitate discharges in nociceptive neurons.

Hyperalgesia

Hyperalgesia was originally defined as “a state of increased intensity of pain sensation induced by either a noxious or ordinarily non-noxious stimulation of peripheral tissue” ( ). Later, the term allodynia was coined for pain in response to normally non-painful stimuli. A very common cause of pain, sensitization of nociceptive nerve endings (“peripheral sensitization”) will, however, always induce both hyperalgesia and allodynia by shifting the stimulus–response curve to lower intensities. Thus, a single neuronal mechanism would be described in terms of two different phenomena—“hyperalgesia” and “allodynia.” Use of these terms is further confused in the literature, where lowering of mechanical withdrawal thresholds (e.g., assessed with von Frey hairs) is typically described as mechanical “allodynia” whereas lowering thermal withdrawal thresholds (e.g., in the hot plate or Hargreaves’ tests) is labeled heat “hyperalgesia” (see also discussion in ). the IASP task force for nomenclature suggested that “hyperalgesia” be used for all forms of increased pain sensitivity (similar to the original definition) and that the term “allodynia” be restricted to pain that is not elicited by nociceptive nerve fibers, that is, pain induced by low-threshold Aβ or C fibers ( , ).

When caused by a peripheral insult, hyperalgesia or allodynia are labeled “primary” at the site of the injury, “secondary” in the immediately surrounding area, and “spreading hyperalgesia” at remote sites. Referred hyperalgesia is localized to the corresponding dermatome of the affected inner organ. Most often no distinction is made between hyperalgesia in humans and “hyper-nociception” in surrogate pain models in animals. In this chapter the new definitions of hyperalgesia and allodynia are used, but not the rather unusual term hyper-nociception.

Neuronal Plasticity

Neuronal plasticity is defined as changes in the properties or functions of neurons or neuronal nets that outlast the stimulus that caused these changes. Note : In the context of pain, neuronal plasticity most often refers to the neural mechanisms of hyperalgesia or allodynia. Lasting forms of analgesia, such as after counter-stimulation, physical therapy, or psychotherapy, do, however, also involve some forms of neuronal plasticity.

Central Sensitization

Stemming from the original term central excitatory state ( ), central sensitization has become a popular phrase in the literature. Unfortunately, it is now used in different and often incompatible definitions that also suffered from considerable metamorphosis over time. The newly proposed definition by the IASP describes “central sensitization” as the “increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input.” Nociceptive neurons may, however, serve very diverse functions (see earlier). Thus, “central sensitization” in the IASP definition may in some cases lead to enhanced pain sensitivity. In other cases, central sensitization may cause analgesia or may simply be unrelated to the experience of pain. Other definitions of central sensitization are equally problematic (see, e.g., discussion in ). The term “central sensitization” is therefore not used in this chapter. It is replaced by more specific technical terms that specify the location (spinal, brain stem, or cortical mechanisms), the underlying mechanism (e.g., synaptic long-term potentiation [LTP] or disinhibition), and the proposed functional meaning (e.g., pain amplification or generation).

Information Flow in Spinal Nociceptive Pathways

Noxious stimuli activate free nerve endings of thinly myelinated Aδ or unmyelinated C fibers. In contrast, most Aβ fibers have low thresholds and respond to innocuous stimuli (see Chapter 1 ). Sensory nerve fibers terminate in the spinal dorsal horn in a modality-specific fashion. Nociceptive Aδ fibers terminate largely in the most superficial lamina I and in the deep lamina V of the spinal dorsal horn, whereas most nociceptive C fibers terminate in laminae I and II _outer . Low-threshold Aβ fibers terminate in lamina II _inner and in laminae III and IV ( ) (see Chapter 5 ). On excitation, apparently all sensory nerve fibers release glutamate. Glutamate is the major fast excitatory neurotransmitter in all nociceptive afferent nerve fibers. Glutamate binds to three types of ionotropic glutamate receptors and to G protein–coupled metabotropic glutamate receptors. Ionotropic glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype are highly permeable to Na ⁺ ions. AMPA receptors lacking the GluR2 subunit are, in addition, also permeable to Ca ²⁺ . Activation of AMPA receptors mediates much of the post-synaptic excitatory currents at glutamatergic synapses. Spinal ionotropic kainate receptors are present pre- and post-synaptically and become activated with strong noxious stimuli. Glutamate receptors of the N -methyl- d -aspartate (NMDA) subtype are highly permeable to Ca ²⁺ ions. NMDA receptors open when glutamate binds to the receptor and when in addition the membrane is sufficiently depolarized to remove the Mg ²⁺ block from the channel pore. NMDA receptors composed of NR1/NR2D subunits have, however, a much-reduced Mg ²⁺ block that renders them permeable to Ca ²⁺ at resting membrane potential ( ). These types of NMDA receptors are expressed in the superficial laminae of the spinal dorsal horn ( ). Activation of NMDA receptors and the resultant Ca ²⁺ influx play pivotal roles in plasticity in the spinal dorsal horn ( ). Some fibers in addition release various neurotransmitters and neuromodulators. The composition of substances released in the spinal dorsal horn depends on the fiber types activated and their discharge frequencies. For example, peptidergic fibers release the neuropeptides substance P or calcitonin gene–related peptide. On high-frequency discharge, some sensory nerve fibers also release brain-derived neurotrophic factor (BDNF). Primary afferents may also release adenosine triphosphate (ATP). After nerve injury some afferents synthesize and release the neuronal chemokine CCL2 and tumor necrosis factor-α (TNF-α). Once released, they bind to their respective synaptic and extrasynaptic receptors on spinal dorsal horn neurons and/or to receptors expressed by spinal glial cells ( ).

Projection neurons within spinal laminae I and V account for most of the nociceptive input to the brain. Spinal projections to thalamic nuclei are considered relevant for the somatosensory–discriminative aspects of pain, whereas projections to the parabrachial area are believed to contribute to the emotional–aversive components of pain. Subconscious and homeostatic reactions to pain, including autonomic responses, are triggered by nociceptive spinal neurons with projections to the nucleus tractus solitarius, the parabrachial area, and the midbrain periaqueductal gray ( ).

A large proportion of nociceptive spinal dorsal horn neurons are interneurons that do not project to the brain. This includes nociceptive spinal dorsal horn neurons that are components of reflex arcs mediating nocifensive withdrawal responses. About one-third of spinal nociceptive neurons use γ-aminobutyric acid (GABA) and/or glycine as neurotransmitters and inhibit other spinal neurons, including projection neurons ( ).

Like neurons, glial cells also respond to nociceptive input. Depending on the type of activation, glial cells release a distinct mélange of neuroactive substances and thereby modify the flow of information in spinal nociceptive pathways. See Chapter 5 of this textbook for more details on the neuroanatomical organization in the spinal dorsal horn.

Spinal processing of nociceptive information is under powerful inhibitory and facilitatory control from brain stem sites with long descending projections to the spinal dorsal horn. Descending neurons use mainly glutamate or the monoamines serotonin or noradrenaline as neurotransmitters in the spinal cord. The inhibition by noradrenaline is either direct or indirect via activation of spinal inhibitory interneurons. Descending modulations of spinal nociception are tonically active, display a circadian rhythm, and can be boosted on demand ( ) (see Chapter 8 for details).

Plasticity in the Spinal Dorsal Horn Contributes to Hyperalgesia or Allodynia

In 1950 the first systematic experimental evidence for central mechanisms of postinjury pain hypersensitivity was provided by Hardy and colleagues. These authors studied the properties of secondary hyperalgesia in human volunteers and came to the conclusion that “secondary hyperalgesia … is the result of a central excitatory state” where subliminal excitations of interneurons in the spinal dorsal horn become suprathreshold and thereby open pre-existing pathways linking the area of primary and secondary hyperalgesia in skin or deep tissues (see Fig. 6-1 , a reproduction of the original figure by ). These authors stated that the “central excitatory state causing secondary hyperalgesia” also leads to longer-lasting pain sensations and can be prevented or reversed by local anesthetic block of impulses in primary afferents from the injured area. In concluded that “referred hyperalgesia … must be occurring in the central nervous system … at the first synaptic relay area in the dorsal horn of the spinal cord.”

Figure 6-1, Schematic diagram of pain fiber connections within the neuron pool showing foci of excitation (stippled area) that result from the continuous barrage of noxious impulses from the site of injury.

The concept of and of a “central excitatory state” was later experimentally adopted by . In unanesthetized decerebrate rats he found that unilateral thermal foot injury induces uni- or bilateral amplification and prolongation of nociceptive flexor reflexes. Furthermore, the discharges of motoneurons and the size of their receptive fields increase. Thereafter, a large number of laboratories have extended the early findings from the spinal ventral horn by exploring potential molecular, cellular, and network mechanisms of hyperalgesia and allodynia first in spinal dorsal horn lamina I projection neurons ( ) and later also in the brain.

In principle, all forms of neuronal plasticity that have been identified in the CNS can also be relevant for nociceptive pathways in the spinal cord and brain. This includes various forms of synaptic plasticity, intrinsic (i.e., membrane) plasticity, and network plasticity in excitatory and inhibitory pathways.

How Plasticity is Induced in the Spinal Dorsal Horn

Plasticity in spinal nociceptive pathways may be induced in various ways. Most often strong and/or sustained activation of nociceptive C fibers, especially from deep tissues ( ), is involved. Ablation of a subgroup of nociceptive afferent fibers that express the transient receptor potential vanilloid-1 (TRPV1) receptor channel ( ) or ablation of virtually all nociceptive afferents identified by Na _v 1.8 expression ( ) does not, however, prevent induction of mechanical hyperalgesia after peripheral nerve injury. This indicates that activation of nociceptive afferents is not always necessary for induction of plasticity in the spinal dorsal horn. Indeed, a recent study claimed that activity in low-threshold mechanosensitive C fibers that express the vesicular glutamate transporter-3 (VGLUT3) triggers mechanical hyperalgesia after injury ( ). Hyperalgesia and allodynia can be further induced in humans in the absence of any sensory stimuli, such as during prolonged application of opioids ( ) or on abrupt withdrawal of opioids ( ). Nonetheless, expression of opioid-induced hyperalgesia requires the presence of TRPV1 receptor-expressing nociceptive afferents ( ).

Substances that Induce Hyperalgesia and/or Allodynia on Spinal Application

The literature provides a large and steadily growing list of molecules that are released into the spinal cord by neuronal or non-neuronal pro-nociceptive helper cells. When applied experimentally onto the spinal cord, some substances are sufficient for the induction of hyperalgesia and/or allodynia. Other substances do not induce but rather facilitate the induction of hyperalgesia. Up to now the effects of individual modulators have almost exclusively been studied in isolation, but their clinically relevant action takes place jointly. It is likely that during the pathogenesis of pain the composition of relevant spinal mediators continuously changes and will be distinct for different types of pain. The presently known signaling pathways probably just reflect the tip of an enormous iceberg of spinal signaling molecules contributing to the pathogenesis of hyperalgesia and allodynia. The matter is further complicated by the fact that the pro-nociceptive effects of a given mediator may be absent or revert to antinociception, depending on the experimental context. Examples are galanin, nociceptin/orphanin FQ, and nerve growth factor (NGF), which may have either pro- or antinociceptive effects in different animal models of hyperalgesia and allodynia ( , , ). Pro-nociceptive spinal mediators include but are not limited to the following substances.

Endogenous Substances

Peptides : Substance P, neurokinin A and B, calcitonin gene–related peptide, dynorphin A, galanin, nociceptin/orphanin FQ, bradykinin, adrenomedullin (for review see )
Proteins : Glycoprotein gp120, thrombin, fibronectin, secretory protein Bv8
Cytokines : TNF-α, interleukin-1β (IL-1β), IL-6, interferon-γ ( , )
Chemotactic cytokines (chemokines) : Fractalkine (CX ₃ CL1); monocyte chemoattractant protein-1 (MCP-1), now known as CCL2
Prostanoids : Prostaglandins E ₁ , E ₂ , D ₂ , F ₂ α ( )
Neurotrophic factors : BDNF, NGF ( )
Miscellaneous: Lipopolysaccharides, platelet-activating factor

Drugs

Modulators of neurotransmitter receptors : Glutamate receptor agonists (at the NMDA, AMPA, kainate, and group I metabotropic glutamate receptors), μ-opioid receptor agonists (on abrupt withdrawal and/or prolonged application), antagonists at GABA _A receptors, agonists at P2X purine receptors (ATP), serotonin acting on 5-HT ₃ receptors
Nitric oxide (NO) pathway : Sodium nitroprusside, hydroxylamine, l -arginine
Activators of kinases : Phorbol esters (for protein kinase C [PKC]), ephrin B1-Fc and B2-Fc (Eph receptor tyrosine kinases)
Chemotherapeutics : Paclitaxel, vincristine, cisplatin, oxaliplatin

These substances trigger different, only partially overlapping spinal signaling pathways, thereby leading to distinct forms of hyperalgesia or allodynia. See for review and references. The complexity of interacting signaling pathways in the neuronal and non-neuronal cellular networks is only beginning to unfold. Unraveling their mutual interactions will constitute a major challenge for the future.

Spinal Cord Cells Indispensible in the Induction of Hyperalgesia and/or Allodynia

A number of cellular elements in the spinal cord have been identified that appear to be necessary for full expression of hyperalgesia or allodynia. C fibers that express either the TRPV1 receptor ( ), the marker isolectin B4 ( ), or VGLUT3 ( ) are, in different contexts, claimed to be essential for the induction of hyperalgesia in some animal models. Selective destruction of dorsal horn neurons that express the neurokinin 1 (NK1) receptor also prevents full expression of hyperalgesia after inflammation or nerve injury ( ). Many of these neurons are located in lamina I and project to the brain. Substances that block the metabolism of microglia and astrocytes (e.g., fluorocitrate) ( ) or microglia only (minocycline) ( ) also block the development of hyperalgesia and allodynia. Spinal fiber tracts that are essential for full expression of hyperalgesia or allodynia include the anterior lateral quadrant ( ), the lateral funiculus ( ), and the dorsal columns ( ).

Playing Schedules on the Spinal Stage of the Pain Theater

The specificity theory of pain assigns the leading part to principal pain neurons. Although the leading actor or actors on the spinal stage have not yet been identified, a number of good candidates have been proposed—namely, nociceptive spinal dorsal horn neurons with a projection to the thalamus, the midbrain periaqueductal gray, and/or the parabrachial area. Excitatory and inhibitory interneurons in the spinal dorsal horn play important roles in modulating the perception of pain. Supporting actors include microglia and astrocytes, blood cells such as T lymphocytes, and perhaps also dural mast cells in their roles as pro-nociceptive helper cells. The roles played by individual actors may change during the pathogenesis of pain. For example, antinociceptive neurons may become excitatory in the course of neuropathy ( ); that is, they may then play the role of pro-nociceptive helper cells. Likewise, glial cells that otherwise fulfill housekeeping functions may become pro-nociceptive helper cells when releasing pro-nociceptive substances after activation. The actors on the spinal stage of nociception communicate with each other (see Fig. 6-2 ). The modes of their interactions will ultimately determine the outcome of the performance (i.e., whether pain is felt by an individual).

Figure 6-2, During nociception, neuronal and non-neuronal cells communicate with each other. The type of nociceptive afferent barrage determines which substances are synthesized and/or released from pre-synaptic nerve terminals, post-synaptic neurons, and glial cells. Under some pathological conditions, the integrity of the blood–spinal cord barrier may be interrupted and thereby allow extravasation of large molecules and blood cells into the spinal parenchyma. Together, the unique mixture and sequence of events determine the type of plasticity that is induced in the spinal dorsal horn.

The repertoire of plasticity in spinal nociceptive circuits ranges from subtle changes in ion channel conductance to drastic changes in the morphology of cells and the connectivity and functions of neuronal networks. The various forms of plasticity include but are not limited to molecular and cellular changes in the number and functional state of synaptic, somal, and axonic ion channels, receptors, enzymes, transporter molecules, and transcription factors. This may lead to alterations in the synthesis, release, and uptake of neurotransmitters and neuromodulators; to synaptic or intrinsic plasticity; and to changes in the cytoskeleton of cells and modifications in cell morphology. Plasticity at the cellular level feeds into functional changes at the network and systemic levels, some of which ultimately lead to altered pain experiences.

In this chapter presently known forms of plasticity in spinal nociceptive pathways are described. It should be kept in mind that the very same type of plasticity may have a different impact on pain, depending on the functions of the affected neurons. For example, disinhibition of principal pain neurons causes hyperalgesia, whereas disinhibition of antinociceptive neurons may have the opposite effect.

Plasticity in Excitatory Nociceptive Pathways of the Spinal Dorsal Horn

Synaptic Plasticity

Synaptic strength describes the magnitude of post-synaptic currents or potentials in response to a pre-synaptic action potential. Synaptic strength may be modified in an activity-dependent manner. For example, high-frequency discharges in pre-synaptic fibers and concomitant strong synaptic activity may lead to a long-lasting increase in synaptic strength. This LTP is a form of synaptic plasticity that can be induced at many, if not all, synapses in the CNS, including spinal synapses of nociceptive primary afferents ( , , , ) and excitatory synapses between spinal lamina II interneurons ( ).

Synaptic Long-Term Potentiation

In nociceptive pathways, LTP may be triggered by enhanced synaptic activity (i.e., in a use-dependent manner) or in the absence of any pre-synaptic activity; for example, by abrupt withdrawal from opioids).

Activity-Dependent Forms of Long-Term Potentiation in Nociceptive Pathways

LTP has been induced at synapses between primary afferent C fibers, many of which are nociceptive, and spinal dorsal horn neurons in vitro and in vivo (see for a review). Conditioning stimuli that induce LTP include injection of capsaicin or formalin into a hindpaw, peripheral inflammation, acute nerve injury, and direct electrical nerve stimulation at high (100 Hz) ( , ) or low (around 2 Hz) frequencies ( ). All these stimuli also induce hyperalgesia in awake animals or human subjects. Some forms of LTP could be induced selectively in spinal lamina I projection neurons ( ) that are essential for full expression of hyperalgesia in awake animals ( , ) and are thus prime candidates for principal pain neurons.

Importantly, perceptual correlates of use-dependent LTP in nociceptive pathways were identified in human volunteers. When cutaneous, peptidergic afferents were stimulated at either high or low frequencies or with capsaicin, primary or secondary hyperalgesia was induced that lasted for several days ( ). Like LTP at spinal lamina I projection neurons, this form of hyperalgesia requires activation of NMDA receptors for its induction ( ).

It is presently unknown whether LTP in nociceptive pathways is homosynaptic in nature (i.e., affects synapses that were activated during the conditioning stimulus). Homosynaptic LTP at principal pain neurons would lead to primary hyperalgesia. If LTP is also expressed at other synapses that impinge on the same principal pain neuron, secondary hyperalgesia would then result. A recent study suggested that activation of C fibers activates silent synapses of Aδ fibers via heterosynaptic facilitation ( ). (See the section entitled Mechanisms of Secondary or Widespread Hyperalgesia, later.)

Drug-Induced Long-Term Potentiation in Nociceptive Pathways

In addition to postinjury forms of hyperalgesia, drug-induced forms are also of considerable clinical relevance. For example, hyperalgesia may develop in human subjects and in experimental animals during the continuous use of opioids ( ) or after abrupt withdrawal of opioids ( ). Opioids acutely depress synaptic strength at C fibers, mainly by pre-synaptic inhibition via interference with N- and P/Q-type voltage-gated calcium channels (VGCCs) ( ). Acute depression of release of neurotransmitters from nociceptive afferents is a major mechanism underlying opioid analgesia. On abrupt withdrawal from opioids (remifentanil, fentanyl, or morphine), synaptic strength not only returns to normal but also may become potentiated for prolonged periods ( , ). Induction of this opioid withdrawal LTP is post-synaptic in nature because it requires activation of post-synaptic G proteins and post-synaptic NMDA receptors and a rise in post-synaptic Ca ²⁺ concentration. It is presently unknown whether LTP also develops during the prolonged application of opioids. The signaling pathways for activity-dependent forms of LTP and opioid withdrawal LTP largely overlap both each other and opioid-induced hyperalgesia. Whereas induction of activity-dependent and opioid withdrawal LTP requires post-synaptic signaling ( ; ), consolidation and maintenance of LTP may involve pre-synaptic mechanisms ( , ).

Additional mechanisms, including descending facilitation from brain stem sites, clearly also play a role in opioid-induced hyperalgesia ( , , ). (See also the section entitled Plasticity in Descending Pathways, later.)

Drugs other than opioids can likewise induce LTP in nociceptive pathways when applied directly onto the spinal cord in vivo. Such substances include ATP, BDNF, the dopamine receptor D ₁ /D ₅ agonist SKF 38393, and the protein kinase A (PKA) activator 8-Br-cyclic adenosine monophosphate (cAMP). In spinalized animals (i.e., when the descending inhibitory pathways are blocked), spinal application of NMDA, substance P, or neurokinin A also induces LTP at C-fiber synapses, whereas TNF-α is effective in neuropathic animals only. For review and references, see the review by .

LTP at the synaptic relay between nociceptive nerve fibers and potential principal pain neurons in the superficial spinal dorsal horn shares induction protocols, pharmacological profiles, and signaling pathways with various forms of hyperalgesia and allodynia. LTP is thus considered a synaptic mechanism of pain amplification ( , ). It is quite likely that similar forms of plasticity exist at synapses upstream in nociceptive pathways, including synapses in the cerebral cortex ( , ).

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