Translational Pain Research: Achievements and Challenges

Mao, Jianren

doi:10.1016/j.jpain.2009.06.002

Cited by 85 publications

(78 citation statements)

References 132 publications

(120 reference statements)

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“…It is acknowledged that both preclinical and clinical research have their unique advantages and specific limitations. 28,29 However, a complementary approach, where findings that are not (or less) repeatable in animals versus humans (and vice versa), should be specifically emphasized to close some gaps between the research models. There are actually only very few comparative studies following either the natural course (spontaneous) of recovery or resulting from novel interventions in SCI.…”

Section: Translation Of Outcome Measuresmentioning

confidence: 99%

The translational dialogue in spinal cord injury research

Curt

2011

Spinal Cord

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Background: Although the emphasis in clinical spinal cord injury (SCI) research has been directed towards the evaluation of clinical assessments (standards in neurological examination) and the appreciation of outcome measures (that is, extent and pattern of clinical recovery from SCI), the underlying neurological mechanisms for recovery from SCI are not well documented in humans. However, to improve the translational research, a meaningful preclinical-clinical dialogue is required, with an appreciation for both fundamental neural mechanisms and what makes human SCI unique. This holds true both for potential interventions in rehabilitation and novel drug or cell-based treatment approaches in acute SCI. Objectives: The gap in translational research that needs to be approached from both ends not only includes the appreciation of principal neural mechanisms (repair, sprouting, plasticity) and their assumed impact onto outcomes (even though humans and non primate animals may rely on slightly different supraspinal control for some movements), but also includes an understanding of the spatial (location and size of lesion) and temporal (timelines of damage and recovery) factors in spinal cord damage that can vary considerably between the different species being studied. Conclusion:The preclinical-clinical dialogue should be encouraged as a venue to improve the appreciation of discoveries in basic research, and to power valid discoveries towards a meaningful translation into advanced treatments downstream. Similarly, the upstream identification of appropriate clinical targets that take into account clinical constraints depends on reliable and advanced clinical information being provided to preclinical investigators.

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Section: Translation Of Outcome Measuresmentioning

confidence: 99%

The translational dialogue in spinal cord injury research

Curt

2011

Spinal Cord

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“…The interaction of many of complex biological pathways is essential for the development of persistent pain, whether inflammatory or neuropathic (2). Thus, numerous available analgesic agents that target a single pathway lack wide-spectrum efficacy and display side effects, which justifies efforts to better understand pain mechanisms (3). Interfering with one of these pathways, the COX branch of the arachidonic acid (ARA) cascade, is a well accepted strategy for reducing inflammatory pain, although COX inhibitors are ineffective in reducing neuropathic pain (4).…”

mentioning

confidence: 99%

Analgesia mediated by soluble epoxide hydrolase inhibitors is dependent on cAMP

Inceoglu

Wagner

Schebb

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

124

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Pain is a major health concern even though numerous analgesic agents are available. Side effects and lack of wide-spectrum efficacy of current drugs justify efforts to better understand pain mechanisms. Stabilization of natural epoxy-fatty acids (EFAs) through inhibition of the soluble epoxide hydrolase (sEH) reduces pain. However, in the absence of an underlying painful state, inhibition of sEH is ineffective. Surprisingly, a pain-mediating second messenger, cAMP, interacts with natural EFAs and regulates the analgesic activity of sEH inhibitors. Concurrent inhibition of sEH and phosphodiesterase (PDE) dramatically reduced acute pain in rodents. Our findings demonstrate a mechanism of action of cAMP and EFAs in the pathophysiology of pain. Furthermore, we demonstrate that inhibition of various PDE isozymes, including PDE4, lead to significant increases in EFA levels through a mechanism independent of sEH, suggesting that the efficacy of commercial PDE inhibitors could result in part from increasing EFAs. The cross-talk between the two major pathways-one mediated by cAMP and the other by EFAs-paves the way to new approaches to understand and control pain.nociception | antinociceptive | epoxyeicosatrienoic acid

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“…Although there are obvious similarities between species, there are also differences. This is not least the case in such a multi-faceted experience as pain, and translating evidence from animals to humans in this field is far from trivial [147]. It is against this background that the quest for human pain biomarkers must be understood.…”

Section: The Quest For Biomarkersmentioning

confidence: 99%

“…Translational research is research that aims to bridge the gap between basic and clinical science [125,147]. Using the practice of ITA at our clinical department as a starting point, the overall aim of this thesis was to conduct translational pain research at the interface between clinical pain medicine and the growing field of human proteomics.…”

Section: Aimsmentioning

confidence: 99%

The Cerebrospinal Fluid in Severe Pain Conditions : Clinical, Pharmacological and Proteomic Aspects

Bäckryd¹

2015

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The treatment of both cancer pain and non-cancer chronic pain is still suboptimal. The overall aim of this PhD thesis was to conduct translational pain research at the interface between clinical pain medicine and the field of human proteomics, using the practice of intrathecal analgesia at our institution as a starting point. Hence, the cerebrospinal fluid (CSF) is at the centre of the present dissertation, both as a target for infusing analgesics (Papers I and II – clinical and pharmacological aspects) and as an important biofluid for human biomarker studies (Papers III and IV – proteomic aspects). In Paper I, 28 cases of intrathecal analgesia in cancer patients were prospectively followed. Movement-evoked breakthrough pain remained a major clinical problem throughout the study month despite otherwise successful intrathecal analgesia (defined as good control of spontaneous resting pain paralleled by a marked decrease of concomitant systemic opioid doses). This study therefore illustrates the importance of considering not only spontaneous resting pain but also movement-evoked breakthrough pain. In Paper II, an expert-based algorithm for trialing the intrathecal analgesic ziconotide by bolus injections was evaluated in an open-label study of 23 patients with chronic neuropathic pain. We found few responders (13%) according to the strict criteria of the algorithm, but ziconotide bolus injection trialing seems feasible. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (with very slow tissue penetration due to high hydrophilicity) calls the rationale for ziconotide bolus trialing into question. In Paper III, we found low levels of beta-endorphin in the CSF of chronic neuropathic pain patients (n=15) compared to healthy controls (n=19). We speculate that this might indicate dysfunctional top-down control of nociception. Substance P levels in the CSF did not differ by univariate statistics. In Paper IV, the CSF proteome of 11 patients with chronic neuropathic pain and 11 healthy controls was exploratively studied, combining gel-based proteomics with multivariate data analysis. After eliminating four proteins associated with age, 32 proteins were found to highly discriminate between groups. Among these, the seven proteins having the highest discriminatory power between patients and controls were: one isoform of angiotensinogen, two isoforms of alpha-1-antitrypsin, three isoforms of haptoglobin, and one isoform of pigment epithelium-derived factor. In conclusion, this PhD thesis demonstrates the fruitfulness of studying the CSF, both as a target for infusing analgesics and as a potential mirror of the neurobiological processes involved in pathological pain conditions. The thesis points to the need for more research into the mechanisms of different pain conditions, in order to hopefully achieve the vision of mechanism-based pain diagnoses

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Translational Pain Research: Achievements and Challenges

Cited by 85 publications

References 132 publications

The translational dialogue in spinal cord injury research

The translational dialogue in spinal cord injury research

Analgesia mediated by soluble epoxide hydrolase inhibitors is dependent on cAMP

The Cerebrospinal Fluid in Severe Pain Conditions : Clinical, Pharmacological and Proteomic Aspects

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