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Long-term potentiation in spinothalamic neurons

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Abstract

Sensitization of nociceptive dorsal horn neurons, including spinothalamic tract (STT) cells, is thought to underlie the development of secondary hyperalgesia and allodynia following tissue injury. In central sensitization, responses to stimulation of sensory receptors are enhanced without any change in the excitability of the primary afferent neurons. We hypothesize that central sensitization of STT neurons is a variety of long-term potentiation (LTP). Evidence that LTP occurs in the spinal cord is reviewed. Neurotransmitters that trigger central sensitization include excitatory amino acids and peptides. Evidence for this is that co-activation of N-methyl-d-aspartate and NK1 receptors can produce long-lasting increases in the responses of STT cells, and antagonists of these receptors prevent central sensitization. Responses to excitatory amino acids increase and those to inhibitory amino acids decrease during central sensitization, presumably accounting for the changed excitability of STT cells. We believe these changes result from the activation of signal transduction pathways, including the protein kinase C, NO/protein kinase G and protein kinase A cascades. Recent evidence shows that calcium/calmodulin dependent kinase II (CaMKII) is also upregulated early in the process of central sensitization and that several types of ionotropic glutamate receptors become phosphorylated. It is proposed that the phosphorylation of neurotransmitter receptors leads to alterations in the sensitivity of these receptors and to central sensitization. Comparable events occur during LTP in brain structures.

Introduction

Strong noxious stimulation can result not only in pain but also in hyperalgesia and allodynia. Hyperalgesia can be defined as “an increased response to a stimulus which is normally painful” and allodynia as “pain due to a stimulus which does not normally provoke pain” [55]. Hyperalgesia and allodynia in an area that has been injured are referred to as primary hyperalgesia and allodynia, whereas hyperalgesia and allodynia in an adjacent, undamaged part of the body are known as secondary hyperalgesia and allodynia [26], [36], [98]. Hyperalgesia and allodynia can be evoked by mechanical and/or thermal stimuli.

In early studies of hyperalgesia and allodynia, summarized in Lewis [36] and in Hardy et al. [26], the skin of human volunteers was damaged by a mild burn, by mechanical injury or by electric shocks. More recently, a number of investigators have employed intradermal injections of capsaicin to produce these pain states [1], [32], [33], [46], [74], [79], [94], [110]. An intradermal injection of capsaicin has the following consequences. Pain is maximal initially but decreases progressively over about 15–20 min. At the injection site, there is a zone of hypesthesia [33], [74] that can be attributed to the excitotoxic or desensitizing effect of the capsaicin on capsaicin-sensitive primary afferent fibers [29], [80], [92]. Primary mechanical and heat hyperalgesia develop rapidly in the vicinity of the injection and persist for about a day. Secondary mechanical hyperalgesia and allodynia develop over a period of about 15 min in a progressively enlarging area of skin surrounding the injection site (Fig. 1), following which they slowly decrease. Depending on the dose of capsaicin that is injected, secondary mechanical allodynia may last several hours and secondary mechanical hyperalgesia about a day.

The generally accepted view concerning the mechanism of primary hyperalgesia is that it reflects the sensitization of nociceptive afferents that supply the area of skin near the damaged site [34], [56]. However, primary afferent fibers that supply the area that develops secondary mechanical hyperalgesia and allodynia maintain a normal level of excitability; that is, they are not sensitized (Refs. [2], [32]; see also Ref. [77]). Thus, secondary mechanical hyperalgesia and allodynia must result from an enhanced responsiveness of central nociceptive neurons or ‘central sensitization’ (see Refs. [100], [102]), rather than from sensitization of primary afferents (Fig. 1). It is likely that central sensitization also contributes to primary hyperalgesia, although peripheral sensitization is the initiating event.

Our laboratory is one of several that have been investigating the mechanisms of secondary hyperalgesia and allodynia (Refs. [51], [53], [96]; see also Ref. [72]). Our experiments have utilized the intradermal injection of capsaicin to initiate central sensitization in spinothalamic tract (STT) neurons recorded in anesthetized monkeys [14], [81], in dorsal horn interneurons recorded in anesthetized rats [103], or in awake, behaving rats [63], [82]. For behavioral experiments, the injection of capsaicin is done during brief anesthesia.

There have been several reports of long-term potentiation (LTP) in the dorsal horn of both in vitro and in vivo preparations of the spinal cord [47], [48], [49], [66], [70], [73], [88], [89], [90], [91]. Similarities to some forms of LTP in the hippocampus include the prolonged time course of the increased responsiveness of the affected neurons and dependence on N-methyl-d-aspartic acid (NMDA) receptors for triggering the process (Fig. 2A–C) (Refs. [47], [49], [66], [70], [73], [91]; see also Ref. [71]). In a commentary on one of the papers by the Norwegian group [99], it was suggested that there are many similarities between central sensitization and LTP that suggest at least partially overlapping mechanisms (see also Refs. [64], [66], [71]). A difference between LTP in the spinal cord and that in the brain is that LTP in the spinal cord depends on the activation of neurokinin receptors (Fig. 2D) [48]. However, other G-protein coupled receptors, such as metabotropic glutamate receptors, can contribute to LTP in the hippocampus.

Section snippets

Experimental design

For studies of the synaptic events that lead to central sensitization, we took advantage of the observation that two successive intradermal injections of capsaicin into neighboring parts of the receptive field of a primate STT cell produced very similar responses, provided that the effects of the first injection were permitted to wear off (Fig. 3C) [16]. This generally takes about 1.5 to 2 h. A chemical agent, such as an antagonist of specific neurotransmitter receptors or an inhibitor of a

Increases in responses to excitatory amino acids

During the central sensitization produced by an injection of capsaicin into the skin, the responses of STT cells to iontophoretic applications of excitatory amino acids are increased (Fig. 6A) [14]. The time course of this effect parallels that of the enhanced responses to mechanical stimulation of the skin. This observation suggests that a reason for the enhanced responses to peripheral stimulation in the face of an unchanged responsiveness of the primary afferent fibers that supply the area

Role of second messenger systems in central sensitization

It is our hypothesis that the basic mechanism for central sensitization of STT cells are these alterations in the responsiveness of STT cells to excitatory and inhibitory amino acids released by primary afferent volleys. A related hypothesis is that the changes in responsiveness of the excitatory and inhibitory amino acid receptors is due to phosphorylation of these receptors as a result of the action of one or more protein kinases). There is evidence that phosphorylation can enhance the

Phosphorylation of NMDA receptors

As already mentioned, we hypothesize that central sensitization following an injection of capsaicin is the result of increased responses of STT cells to excitatory amino acids and reduced responses to inhibitory amino acids. We have investigated the possibility that NMDA receptors become phosphorylated following capsaicin injection, since it is known that the NMDA currents in neurons isolated from the trigeminal caudalis nucleus are increased when PKC is injected intracellularly during whole

Acknowledgements

The author thanks colleagues with whom he has collaborated over the years. He also thanks Griselda Gonzales for her help with the illustrations. The work in the author’s laboratory has been supported by NIH Grants NS 09743 and NS 11255.

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