Review
Spinal systems and pain processing: development of novel analgesic drugs with mechanistically defined models

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Abstract

Much research has been undertaken in the field of pain in an attempt to find an effective treatment. Insights into the underlying mechanisms of pain have been gained from studies using preclinical animal models (acute stimuli, post-tissue injury and peripheral nerve injury) and evaluating their similarity with the human condition. In this article, these pain models are summarized and the mechanisms of pain discussed in relation to spinal processing. In the context of this research the therapeutic potential of novel analgesics is highlighted as the future looks forward to the many possibilities that the targeted spinal delivery of drugs can bring.

Section snippets

Models of nociceptive processing

As outlined in Table 1, pain models can be broadly separated into three functional divisions based on our current understanding of their underlying mechanisms and pharmacology. Importantly, the ability to assign a mechanism to a model allows the formulation of predictive hypotheses relating to the physiology and pharmacology of the linkages mediating the behavioural profile and to compare these mechanisms to those noted in human pain conditions.

Preclinical models

Following peripheral nerve injury, hyperalgesia and allodynia have been observed. The physiological mechanisms responsible for these phenomena are complex, but they can be divided into several categories. (1) Spontaneous activity develops in the injured terminal (neuroma) and in the dorsal root ganglion cell (DRG) of the injured axon10. (2) Large primary afferents (Aβ) can sprout from laminae III into laminae I and II (11, 12). (3) DRGs display a pericellular basket composed of post-ganglionic

Preclinical models for spinal drug delivery

To assess the pharmacology of spinal systems that mediate these states of nociception, models permitting reliable spinal delivery of agents percutaneously and by chronic catheters have been developed. Catheters can either be externalized to allow repeated spinal injection or terminated subcutaneously and connected to infusion systems26. Because spinally delivered drugs can be redistributed to brainstem sites by rostral redistribution and to the periphery by vascular absorption, appropriate

Pharmacological strategies for regulating spinal nociceptive processing

On the basis of the above considerations, the pharmacological regulation of pain behaviour in the context of the systems involved can be approached at the spinal level of encoding. Mechanistically, these aims can be summarized in the context of: (1) acute small afferent activation; (2) repetitive small-afferent activation after tissue injury, and (3) trophic changes in primary afferent function and connectivity in the dorsal horn after nerve injury. Spinal pharmacological interventions that

Summary

Insofar as the spinal cord is concerned, the correlation between predicted activity and the hypothesized underlying mechanism in preclinical studies provides a degree of validation for the role played by certain spinal transmitter or receptor systems in nociceptive processing. The parallels between preclinical activity after spinal delivery in specific preclinical models and certain human pain states provide two insights. First, the ability of preclinical models to predict human efficacy

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