Jürgen Sandkühler

Models and Mechanisms of Hyperalgesia and Allodynia

Hyperalgesia and allodynia are frequent symptoms of disease and may be useful adaptations to protect vulnerable tissues. Both may, however, also emerge as diseases in their own right. Considerable progress has been made in developing clinically relevant animal models for identifying the most significant underlying mechanisms. This review deals with experimental models that are currently used to measure (sect. II) or to induce (sect. III) hyperalgesia and allodynia in animals. Induction and expression of hyperalgesia and allodynia are context sensitive. This is discussed in section IV. Neuronal and nonneuronal cell populations have been identified that are indispensable for the induction and/or the expression of hyperalgesia and allodynia as summarized in section V. This review focuses on highly topical spinal mechanisms of hyperalgesia and allodynia including intrinsic and synaptic plasticity, the modulation of inhibitory control (sect. VI), and neuroimmune interactions (sect. VII). The scientific use of language improves also in the field of pain research. Refined definitions of some technical terms including the new definitions of hyperalgesia and allodynia by the International Association for the Study of Pain are illustrated and annotated in section I.

Learning and memory in pain pathways

The neurons of the central nervous system not only have the capacity to transmit, inhibit and weigh information, but they may also store information for prolonged periods of time (e.g. by use-dependent change in synaptic strength). Synaptic plasticity in hippocampus is an extensively studied cellular model of learning and memory and recent studies suggest that similar mechanisms also apply to pain pathways and may account for some forms of hyperalgesia, allodynia and analgesia. The discovery of synaptic longterm plasticity in nociceptive systems provides a relatively simple and straight forward concept for a number of clinically relevant phenomena. Here, I will brie y summarize key aspects of synaptic plasticity in general. Then I will describe related changes at nociceptive synapses and discuss the potential relevance of these mechanisms for the development, the prevention and the treatment of chronic pain.

Synaptic Amplifier of Inflammatory Pain in the Spinal Dorsal Horn

Inflammation and trauma lead to enhanced pain sensitivity (hyperalgesia), which is in part due to altered sensory processing in the spinal cord. The synaptic hypothesis of hyperalgesia, which postulates that hyperalgesia is induced by the activity-dependent long-term potentiation (LTP) in the spinal cord, has been challenged, because in previous studies of pain pathways, LTP was experimentally induced by nerve stimulation at high frequencies (∼100 hertz). This does not, however, resemble the real low-frequency afferent barrage that occurs during inflammation. We identified a synaptic amplifier at the origin of an ascending pain pathway that is switched-on by low-level activity in nociceptive nerve fibers. This model integrates known signal transduction pathways of hyperalgesia without contradiction.

INDUCTION OF LONG-TERM POTENTIATION AT SPINAL SYNAPSES BY NOXIOUS STIMULATION OR NERVE INJURY

Use‐dependent long‐term potentiation of synaptic strength (LTP) is an intensively studied model for learning and memory in vertebrates. Induction of LTP critically depends on the stimulation parameters of presynaptic fibres with synchronous high‐frequency bursts being most effective at many central synapses. It is, however, not known whether naturally occurring discharge patterns may induce LTP and whether LTP has any biological function in sensory systems. Here we have investigated the LTP of excitatory synaptic transmission between primary afferent C‐fibres, many of which are nociceptors, and neurons in rat superficial spinal dorsal horn. LTP that lasted for 4–6 h could not only be induced by electrical stimulation of sural nerve but also by natural stimulation of heat‐, mechano‐ or chemosensitive nociceptors in the skin or by acute nerve injury. Maintenance of LTP was not affected when afferent nerves were cut 1 h or 5 min after noxious skin stimulation, indicating that an ongoing afferent barrage is not required. Natural noxious stimuli induced LTP in animals which were spinalized but were ineffective in intact animals. Thus, induction of LTP is suppressed by tonically active supraspinal descending systems. We conclude that the natural non‐synchronized discharge patterns that are evoked by noxious stimulation may induce LTP and that this new form of LTP may be an underlying mechanism of afferent induced hyperalgesia.

Relative contributions of the nucleus raphe magnus and adjacent medullary reticular formation to the inhibition by stimulation in the periaqueductal gray of a spinal nociceptive reflex in the pentobarbital-anesthetized rat

The organization in the brainstem of descending pathways of spinal inhibition was examined in the lightly pentobarbital-anesthetized rat. Thresholds for focal electrical stimulation-produced inhibition of the spinal nociceptive tail flick (TF) reflex were determined at one stimulation site in the midbrain periaqueductal gray and three sites in the rostral medulla: nucleus raphe magnus, and the adjacent medullary reticular formation contralateral and ipsilateral to the stimulating electrode in the periaqueductal gray. Lidocaine (0.5 microliter, 4%) was subsequently microinjected in the same and other medullary loci in the same coronal plane to produce a time-limited, reversible functional neural block. The functional block produced by 0.5 microliter of lidocaine microinjected in the medulla was determined to have a radius of 0.5 mm and was maximally efficacious during the first 30 min after its intramedullary microinjection. The stimulation threshold in the periaqueductal gray for inhibition of the TF reflex was not increased significantly when either the nucleus raphe magnus was fully blocked by lidocaine microinjected in three dorsoventral positions 1.0 mm apart or when the medullary reticular formation ipsilateral and contralateral were simultaneously fully blocked. Not until the nucleus raphe magnus and medullary reticular formation ipsilateral were simultaneously blocked by lidocaine was the stimulation threshold in the periaqueductal gray for inhibition of the TF reflex significantly increased. An increase in the periaqueductal gray stimulation threshold twice as great resulted when the nucleus raphe magnus and both the ipsilateral and contralateral medullary reticular formations were all simultaneously blocked by lidocaine. These results indicate that: (1) the nucleus raphe magnus is not a necessary bulbar relay in a descending antinociceptive pathway activated by stimulation in the midbrain periaqueductal gray; and (2) descending inhibitory pathways activated in the periaqueductal gray course medially as well as laterally in the rat ventral medulla.

Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans.

Long-term potentiation (LTP) and long-term depression (LTD) of synaptic strength are ubiquitous mechanisms of synaptic plasticity, but their functional relevance in humans remains obscure. Here we report that a long-term increase in perceived pain to electrical test stimuli was induced by high-frequency electrical stimulation (HFS) (5 × 1 sec at 100 Hz) of peptidergic cutaneous afferents (27% above baseline, undiminished for >3 hr). In contrast, a long-term decrease in perceived pain (27% below baseline, undiminished for 1 hr) was induced by low-frequency stimulation (LFS) (17 min at 1 Hz). Pain testing with punctate mechanical probes (200 μm diameter) in skin adjacent to the HFS–LFS conditioning skin site revealed a marked twofold to threefold increase in pain sensitivity (secondary hyperalgesia, undiminished for >3 hr) after HFS but also a moderate secondary hyperalgesia (30% above baseline) after strong LFS. Additionally, HFS but not LFS caused pain to light tactile stimuli in adjacent skin (allodynia). In summary, HFS and LFS stimulus protocols that induce LTP or LTD in spinal nociceptive pathways in animal experiments led to similar LTP- and LTD-like changes in human pain perception (long-term hyperalgesia or hypoalgesia) mediated by the conditioned pathway. Additionally, secondary hyperalgesia and allodynia in adjacent skin induced by the HFS protocol and, to a minor extent, also by the LFS protocol, suggested that these perceptual changes encompassed an LTP-like heterosynaptic facilitation of adjacent nociceptive pathways by a hitherto unknown mechanism.

Long-term potentiation of C-fiber-evoked potentials in the rat spinal dorsal horn is prevented by spinal N-methyl-D-aspartic acid receptor blockage.

Long-term potentiation (LTP) of synaptic potentials is a fundamental mechanism of memory formation in the hippocampus. Here, we have characterized long-term changes of field potentials which were evoked in the lumbar spinal dorsal horn by supramaximal electrical stimulation of the sciatic nerve in urethane anesthetized rats. The field potentials had high thresholds (> or = 7 V), long latencies (90-130 ms, corresponding to conduction velocities between 1.2 and 0.85 m/s) and were not affected by spinalization (at C5-C6) or muscle relaxation (with pancuronium), i.e. the potentials were probably evoked by afferent C-fibers. Tetanic electrical stimulation (0.5 ms pulses, 30-40 V, 100 Hz, given in 4 trains of 1 s duration at 10 s intervals) of sciatic nerve induced in all 9 rats tested a LTP of amplitude of the C-fiber-evoked potential throughout recording periods which lasted between 4 and 9 h. Mean potentiation ranged from +71% to +174%. Superfusion of spinal cord with N-methyl-D-aspartic acid (NMDA) receptor antagonist D-(-)-4-(3-phosphonopropyl)piperazine-2-carboxylic (500 nM), which has little effect on the amplitude of C-fiber-evoked potentials, completely blocked LTP induced by tetanic stimulation in all five rats tested. Superfusion of spinal cord with NMDA (1 microM, 10 microM or 50 microM) induced LTP in only 2 out of 8 rats. This is the first report showing that LTP of C-fiber-evoked field potentials in the spinal dorsal horn in vivo may last for more than 8 h. This LTP in the spinal dorsal horn may underlie plastic changes of spinal nociception.

The organization and function of endogenous antinociceptive systems

Much progress has been made the understanding of endogenous pain-controlling systems. Recently, new concepts and ideas which are derived from neurobiology, chaos research and from research on learning and memory have been introduced into pain research and shed further light on the organization and function of endogenous antinociception. These most recent developments will be reviewed here. Three principles of endogenous antinociception have been identified, as follows. (1) Supraspinal descending inhibition: the patterns of neuronal activity in diencephalon, brainstem and spinal cord during antinociceptive stimulation in midbrain periaqueductal gray (PAG) or medullary nucleus raphe magnus have now been mapped on the cellular level, using the c-Fos technique. Results demonstrate that characteristic activity patterns result within and outside the PAG when stimulating at its various subdivisions. The descending systems may not only depress mean discharge rates of nociceptive spinal dorsal horn neurons, but also may modify harmonic oscillations and nonlinear dynamics (dimensionality) of discharges. (2) Propriospinal, heterosegmental inhibition: antinociceptive, heterosegmental interneurons exist which may be activated by noxious stimulation or by supraspinal descending pathways. (3) Segmental spinal inhibition: a robust long-term depression of primary afferent neurotransmission in A delta fibers has been identified in superficial spinal dorsal horn which may underlie long-lasting antinociception by afferent stimulation, e.g. by physical therapy or acupuncture.

Characterization of inhibition of a spinal nociceptive reflex by stimulation medially and laterally in the midbrain and medulla in the pentobarbital-anesthetized rat.

Inhibition of the spinal nociceptive tail flick (TF) reflex by electrical stimulation throughout the midbrain and medulla was examined and characterized in pentobarbital-anesthetized rats. The TF reflex in the lightly anesthetized state is of significantly shorter latency (1.63 s vs 2.36 s) and of greater amplitude than in the unanesthetized state. Systematic mapping studies revealed that inhibition of the TF reflex could be produced from widespread areas in the midbrain and medulla. Midbrain areas having the lowest thresholds for inhibition of the TF reflex were found lateral and ventrolateral to the periaqueductal gray matter, including nucleus cuneiformis, the lateral reticular formation, and extending into the central tegmental area. In the rostral medulla, the lowest thresholds for inhibition of the TF were distributed mediolaterally across the dorsal one-third of the nucleus raphe magnus and into the adjacent nucleus reticularis gigantocellularis. Thresholds for inhibition of the TF reflex were slightly higher in the ventral nucleus raphe magnus and adjacent nucleus reticularis paragigantocellularis. Chronaxies of stimulation in the midbrain and medulla were virtually the same, indicating that the same neural elements were affected by stimulation in both brainstem areas. The thresholds of stimulation for inhibition of the TF reflex in the lightly anesthetized state were not significantly different from the thresholds of stimulation at the same midbrain sites in the awake state in the same animals. These findings contribute to a growing body of literature establishing (1) the utility of the lightly pentobarbital-anesthetized rat model for investigations of antinociceptive mechanisms and (2) the presence of multiple loci and pathways in the brainstem capable of modulating spinal nociceptive processes.

The use of local anaesthetic microinjections to identify central pathways: a quantitative evaluation of the time course and extent of the neuronal block

SummaryThe time course and extent of local anaesthetic blocks within the spinal cord of cats were evaluated. A monopolar stimulation electrode with the tip lowered into the dorsal columns (DC) 1000 μm below cord surface was used to activate antidromically DC fibers at the T13 level and evoke cord dorsum potentials at the level of the lumbar spinal cord. The amplitude of the negative deflection, the N-wave, was determined for various stimulation intensities (stimulation-response-function, SRF). Lidocaine (1%) was microinjected in volumes of 0.5 or 1.0 μl into the DC from a glass micropipette 1 mm caudal to the stimulation site. Conduction block was characterized by a reversible shift of the SRFs to higher stimulation intensities. The diameter of the blocked area in the transverse plane was evaluated from threshold intensities and was found to be 0.9±0.1 mm 4 to 30 min after the injection of 0.5 μl lidocaine and 1.6±0.36 mm 10 to 45 min after the injection of 1.0 μl lidocaine. In the sagittal plane, the diameter of the blocked area following 1.0 μl lidocaine was found to be up to 2.8 mm. The DC-block was reversible within 92 min following injection of 1.0 μl and 69 min after the injection of 0.5 μl lidocaine. The application of the present findings for blocks in other CNS structures is discussed.