Restoring the Spinal Pain Gate

Zeilhofer, Hanns Ulrich; Ralvenius, William T.; Acuña, Mario A.

doi:10.1016/bs.apha.2014.11.007

Cited by 39 publications

(8 citation statements)

References 94 publications

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“…It was recently found that flupirtine acts to enhance GABA-mediated currents at concentrations comparable to those enhancing Kv7 activity 233 . Because GABAA channels are highly diverse in terms of subunit structure (being pentameric combinations of 19 different potential subunits) with different combinations in different neurons and sub-cellular regions, which is still very incompletely understood, it may be possible to find agents with selectivity for specific subunit combinations that enhance pain-relief properties relative to sedation 234 . A better understanding of expression patterns of specific GABAA receptor subunit combinations in the higher-order neuronal pain-mediating circuitry would be useful for a rational approach in this direction.…”

Section: Ion Channels As Drug Targetsmentioning

confidence: 99%

Breaking barriers to novel analgesic drug development

Yekkirala

Roberson

Bean

et al. 2017

Nat Rev Drug Discov

282

246

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Acute and chronic pain complaints, while very common, are generally poorly served by existing therapies. The unmet clinical need reflects the failure in developing novel classes of analgesics with superior efficacy, diminished adverse effects and a lower abuse liability than those currently available. Reasons for this include the heterogeneity of clinical pain conditions, the complexity and diversity of underlying pathophysiological mechanisms coupled with the unreliability of some preclinical pain models. However, recent advances in our understanding of the neurobiology of pain are beginning to offer opportunities to develop new therapeutic strategies and revisit existing targets, including modulating ion channels, enzymes and GPCRs.

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Section: Ion Channels As Drug Targetsmentioning

confidence: 99%

Breaking barriers to novel analgesic drug development

Yekkirala

Roberson

Bean

et al. 2017

Nat Rev Drug Discov

282

246

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“…The importance of μ 2-dependent endocytosis on GABA A Cl channel function is particularly interesting given the role of GABA A Cl channel in nociception. In particular, multiple studies show that GABA agonists are antinociceptive in preclinical models of neuropathic pain but not human pain, perhaps due to dose-limiting sedation or tolerance (reviewed in McCarson and Enna, 2014; Zeilhofer et al, 2015). The antinociceptive activity of GABA A agonists has been localized to the spinal cord, where GABA A receptors are found on primary sensory neurons and intrinsic dorsal horn neurons.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

Kostich

Hamman²,

Li³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

127

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To identify novel targets for neuropathic pain, 3097 mouse knockout lines were tested in acute and persistent pain behavior assays. One of the lines from this screen, which contained a null allele of the adapter protein-2 associated kinase 1 (AAK1) gene, had a normal response in acute pain assays (hot plate, phase I formalin), but a markedly reduced response to persistent pain in phase II formalin. AAK1 knockout mice also failed to develop tactile allodynia following the Chung procedure of spinal nerve ligation (SNL). Based on these findings, potent, small-molecule inhibitors of AAK1 were identified. Studies in mice showed that one such inhibitor, LP-935509, caused a reduced pain response in phase II formalin and reversed fully established pain behavior following the SNL procedure. Further studies showed that the inhibitor also reduced evoked pain responses in the rat chronic constriction injury (CCI) model and the rat streptozotocin model of diabetic peripheral neuropathy. Using a nonbrain-penetrant AAK1 inhibitor and local administration of an AAK1 inhibitor, the relevant pool of AAK1 for antineuropathic action was found to be in the spinal cord. Consistent with these results, AAK1 inhibitors dose-dependently reduced the increased spontaneous neural activity in the spinal cord caused by CCI and blocked the development of windup induced by repeated electrical stimulation of the paw. The mechanism of AAK1 antinociception was further investigated with inhibitors of α2 adrenergic and opioid receptors. These studies showed that α2 adrenergic receptor inhibitors, but not opioid receptor inhibitors, not only prevented AAK1 inhibitor antineuropathic action in behavioral assays, but also blocked the AAK1 inhibitor–induced reduction in spinal neural activity in the rat CCI model. Hence, AAK1 inhibitors are a novel therapeutic approach to neuropathic pain with activity in animal models that is mechanistically linked (behaviorally and electrophysiologically) to α2 adrenergic signaling, a pathway known to be antinociceptive in humans.

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“…glutamate decarboxylase), and altered properties of GABA A receptors, glycinergic receptors and cation-chloride cotransporters 69, 92 . Restoring spinal cord inhibition by, for example, suptype-specific GABA receptor agonists, may offer the opportunity to reduce pain without limiting side effects like sedation 162 .…”

Section: Pain Mechanisms (Table 2)mentioning

confidence: 99%

“…However, recent work on different GABA A receptor subunits has revealed the α2 subunit as a pharmacological target which produces strong antihyperalgesia with reduced sedation, encouraging development of subunit specific GABA A receptor benzodiazepines 162 .…”

Section: Pain Mechanisms (Table 2)mentioning

confidence: 99%

Toward a Mechanism-Based Approach to Pain Diagnosis

Vardeh

Mannion

Woolf

2016

The Journal of Pain

255

166

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The last few decades have witnessed a huge leap forward in our understanding of the mechanistic underpinnings of pain, both in normal states where it helps protect from injury, and in pathological states where pain evolves from a symptom reflecting tissue injury to become the disease itself. However, despite these scientific advances, chronic pain remains extremely challenging to manage clinically. While the number of potential treatment targets has grown substantially and a strong case has been made for a mechanism-based and individualized approach to pain therapy, arguably clinicians are not much more advanced now than 20 years ago, in their capacity to either diagnose or effectively treat their patients. The gulf between pain research and pain management is as wide as ever. We are still currently unable to apply an evidence-based approach to chronic pain management that reflects mechanistic understanding, and instead, clinical practice remains an empirical and often unsatisfactory journey for patients, whose individual response to treatment cannot be predicted. Here we take a common and difficult to treat pain condition, chronic low back pain, and use its presentation in clinical practice as a framework to highlight what is known about pathophysiological pain mechanisms and how we could potentially detect these to drive rational treatment choice. We discuss how present methods of assessment and management still fall well short, however, of any mechanism-based or precision-medicine approach. Nevertheless, substantial improvements in chronic pain management could be possible if a more strategic and coordinated approach were to evolve, one designed to identify the specific mechanisms driving the presenting pain phenotype. We present an analysis of such an approach, highlighting the major problems in identifying mechanisms in patients, and develop a framework for a pain diagnostic ladder that may prove useful in the future, consisting of successive identification of three steps: pain state, pain mechanism and molecular target. Such an approach could serve as the foundation for a new era of individualized/precision pain medicine. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) and American Pain Society (APS) Pain Taxonomy (AAPT) includes pain mechanisms as one of the 5 dimensions that need to be considered when making a diagnostic classification. The diagnostic ladder proposed in this article is both consistent with and an extension of the AAPT.

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Restoring the Spinal Pain Gate

Cited by 39 publications

References 94 publications

Breaking barriers to novel analgesic drug development

Breaking barriers to novel analgesic drug development

Inhibition of AAK1 Kinase as a Novel Therapeutic Approach to Treat Neuropathic Pain

Toward a Mechanism-Based Approach to Pain Diagnosis

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