Allodynia and hyperalgesia within dermatomes caudal to a spinal cord injury in primates and rodents

doi:10.1016/S0079-6123(00)29032-8

Progress in Brain Research

Volume 129, 2000, Pages 411-428

https://doi.org/10.1016/S0079-6123(00)29032-8 Get rights and content

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This chapter discusses allodynia and hyperalgesia within dermatomes caudal to a spinal cord injury in primates and rodents. Persistent pain of central nervous system origin is a common consequence of spinal cord injury and is highly refractory to treatment. In order to understand mechanisms and develop treatments for this condition, an effective laboratory animal model is needed. Clinical observations indicate that interruption of the spinothalamic tract is a prerequisite for development of deafferentation zone pain referred to segments well below the site of spinal cord injury. Therefore, a series of studies has evaluated nociceptive responses of monkeys and rats before and after an anterolateral spinal lesion. Attention to the variability of responses to a wide range of stimulus intensities across testing sessions has shown that contralateral sensitivity oscillates from nearly analgesic to allodynic. All animals cycled between these states of hyper- or hypo-sensitivity. Information from animal model and observations of human beings indicate that superficial lesions of lateral spinal cord white matter that do not extend into the gray matter produce an enduring contralateral hypoalgesia, with minimal allodynia and/or central pain.

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Central neuropathic pain (CNP) was long held to be a psychiatric condition. People with CNP as a result of spinal cord injury (SCI) were marginalized partly due to a shortened life expectancy up until the early 1950s and later because the condition was thought to be psychosomatic. In fact, evidence-based research demonstrates many peripheral and central mechanisms contribute to CNP after SCI, which is clearly not psychosomatic but spinally and supraspinally mediated by permanent somatosensory circuit changes. This chapter begins with a brief history, reviews pain terminology, describes types of neuropathic pain after SCI, considers the challenges of developing mammalian models of CNP after SCI, and then presents the pathophysiology of SCI. For the purposes of the presentation of the progression of the pathophysiology after SCI, the time line post-SCI is the following: (1) immediate, primary injury response; (2) early acute mechanisms that occur minutes to hours; (3) subacute mechanisms that occur over days and weeks; (4) chronic mechanisms that persist when the “wound healing” has subsided. Several mechanisms of CNP are discussed in the temporal progression of the pathophysiology of SCI. Incorporated into the discussions are interventions that may prove successful in treating not only CNP after SCI but also CNP from other causes. Future directions are suggested in the closing paragraphs. In conclusion, CNP after SCI is clearly not psychogenic but a product of very real pathophysiological mechanisms that offer opportunities for treatment and a life free of pain.
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Altered sensations, including pain, are well-documented consequences associated with spinal cord injury. Although loss of sensory and motor function at and below the level of injury are commonly thought to have the most significant impact on individuals with spinal injury, secondary consequences including spasticity, bladder and bowel dysfunction, infertility, and pain rank among the most difficult consequences to deal with following injury. Understanding the mechanism(s) responsible for the condition of pain requires an appreciation for the pathological, physiological, neurochemical, and molecular events associated with injury of the cord parenchyma. The development of injury models to study these events in combination with clinical studies have provided insights into the spinal and supraspinal changes that contribute to the development and maintenance of at- and below-level pain. At the site of injury excitotoxic and inflammatory cascades impact the survivability and functional state of spinal neurons. Changes in the excitability of sensory neurons together with a decrease in local and descending inhibitory influences are thought to lead to the development of a pain-generating mechanism in the cord. Not to be ignored are the anatomical and functional changes occurring at supraspinal sites that are also likely contributors to the mechanism of injury-induced pain.
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Most laboratory animal studies of nociception have evaluated spinal flexion/withdrawal reflexes, despite the inability of reflex tests to assess pain sensitivity. Because multiple reviews address the inherent failings of reflex tests to reveal pain,372-374,379,381,382,386 we need not do that in this article. Put simply, reflex tests assess spinal processing of nociceptive input to spinal interneurons within reflex circuits that output directly to motoneurons to evoke responses that occur before or long after pain sensations occur, depending on the stimulus.386
The nature of the transition from acute to chronic pain still eludes explanation, but chronic pain resulting from surgery provides a natural experiment that invites clinical epidemiological investigation and basic scientific inquiry into the mechanisms of this transition. The primary purpose of this article is to review current knowledge and hypotheses on the transition from acute to persistent postsurgical pain, summarizing literature on clinical epidemiological studies of persistent postsurgical pain development, as well as basic neurophysiological studies targeting mechanisms in the periphery, spinal cord, and brain. The second purpose of this article is to integrate theory, information, and causal reasoning in these areas. Conceptual mapping reveals 5 classes of hypotheses pertaining to pain. These propose that chronic pain results from: 1) persistent noxious signaling in the periphery; 2) enduring maladaptive neuroplastic changes at the spinal dorsal horn and/or higher central nervous system structures reflecting a multiplicity of factors, including peripherally released neurotrophic factors and interactions between neurons and microglia; 3) compromised inhibitory modulation of noxious signaling in medullary-spinal pathways; 4) descending facilitatory modulation; and 5) maladaptive brain remodeling in function, structure, and connectivity. The third purpose of this article is to identify barriers to progress and review opportunities for advancing the field. This review reveals a need for a concerted, strategic effort toward integrating clinical epidemiology, basic science research, and current theory about pain mechanisms to hasten progress toward understanding, managing, and preventing persistent postsurgical pain.
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SCI can also result in the development of either diffuse of bilateral chronic, hyperpathic pain originating below the denervated spinal segment [3–5]. Pain following SCI is categorized according to the region of hypersensitivity with respect to the level of denervation: above-level (forelimbs), at-level (girdling), or below-level (hind limbs) [6,7]. Chronic SCI-pain occurs immediately and increases in intensity over a long period of time following the initial injury [5,8,9].
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Operant escape reveals increased pain sensitivity following sham surgery for bilateral CCI and for SNL, but reflex tests are not affected by the tissue injury associated with unilateral CCI and SNL surgeries. Operant escape testing has consistently confirmed clinical evidence from humans (King, 1957; White and Sweet, 1969) that interruption of the lateral spinothalamic tract initially produces contralateral hypoalgesia, below the level of the lesion (Vierck et al., 1971, 1983b, 1986, 1990, 1995, 2000; Vierck and Light, 1999, 2000, 2002; Vierck and Luck, 1979). In contrast to the contralateral reduction of pain sensitivity, flexion/withdrawal reflexes are depressed bilaterally for the same animals.
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