Neuropathic Pain: Molecular Complexity Underlies Continuing Unmet Medical Need.

Neuropathic pain (NP) represents an unmet medical need, where analgesic responses to different epidermal growth factor receptor inhibitors (EGFR-Is) have been described. The human EGFR family of receptors consists of four members (human epidermal growth factor receptor, HER 1–4), signalling via different homodimer and heterodimer combinations. A 52-year-old man was treated with the EGFR-I cetuximab in a trial of severe NP. Pain scores decreased dramatically after blinded cetuximab, but not after placebo. On pain recurrence after the trial, he was prescribed the oral EGFR-Is erlotinib, gefitinib, and lapatinib without relief. However, treatment with the pan-HER-inhibitor afatinib was effective. After 4 years on afatinib, pain control remains excellent with manageable side effects. This is the first reported observation of differential effects of EGFR-Is on NP in the same patient and the first report describing NP relief with afatinib. Further understanding of the underlying pathophysiology could lead to development of EGFR-Is specifically targeting NP.

Download Full-text

HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain

Biochemical Journal ◽

10.1042/bcj20160287 ◽

2016 ◽

Vol 473 (18) ◽

pp. 2717-2736 ◽

Cited By ~ 23

Author(s):

Christoforos Tsantoulas ◽

Elizabeth R. Mooney ◽

Peter A. McNaughton

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Ion Channels ◽

Warning Signal ◽

Sensory Nerves ◽

Nociceptive Neurons ◽

Pain Syndromes ◽

Medical Need ◽

Pathological Pain ◽

Genetic Deletion

Nociception — the ability to detect painful stimuli — is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a ‘pacemaker for pain’, in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.

Download Full-text

The glial modulatory drug AV411 attenuates mechanical allodynia in rat models of neuropathic pain

Neuron Glia Biology ◽

10.1017/s1740925x0700035x ◽

2006 ◽

Vol 2 (4) ◽

pp. 279-291 ◽

Cited By ~ 76

Author(s):

Annemarie Ledeboer ◽

Tongyao Liu ◽

Jennifer A. Shumilla ◽

John H. Mahoney ◽

Sharmila Vijay ◽

...

Keyword(s):

Neuropathic Pain ◽

Mechanical Allodynia ◽

Cell Activation ◽

Therapeutic Agent ◽

Chronic Constriction Injury ◽

Phosphodiesterase Inhibitor ◽

Spinal Nerve ◽

Spinal Nerve Ligation ◽

Glial Cell Activation ◽

Medical Need

AbstractControlling neuropathic pain is an unmet medical need and we set out to identify new therapeutic candidates. AV411 (ibudilast) is a relatively nonselective phosphodiesterase inhibitor that also suppresses glial-cell activation and can partition into the CNS. Recent data strongly implicate activated glial cells in the spinal cord in the development and maintenance of neuropathic pain. We hypothesized that AV411 might be effective in the treatment of neuropathic pain and, hence, tested whether it attenuates the mechanical allodynia induced in rats by chronic constriction injury (CCI) of the sciatic nerve, spinal nerve ligation (SNL) and the chemotherapeutic paclitaxel (Taxol¯). Twice-daily systemic administration of AV411 for multiple days resulted in a sustained attenuation of CCI-induced allodynia. Reversal of allodynia was of similar magnitude to that observed with gabapentin and enhanced efficacy was observed in combination. We further show that multi-day AV411 reduces SNL-induced allodynia, and reverses and prevents paclitaxel-induced allodynia. Also, AV411 cotreatment attenuates tolerance to morphine in nerve-injured rats. Safety pharmacology, pharmacokinetic and initial mechanistic analyses were also performed. Overall, the results indicate that AV411 is effective in diverse models of neuropathic pain and support further exploration of its potential as a therapeutic agent for the treatment of neuropathic pain.

Download Full-text

Dose and administration-period play a key role in the effect of ceftriaxone on neuropathic pain in CCI-operated rats

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2012.05.035 ◽

2012 ◽

Vol 3 (3) ◽

pp. 186-186 ◽

Cited By ~ 1

Author(s):

K.K. Frederiksen ◽

P. Kristensen ◽

P.H. Honoré ◽

G. Gegelashvili ◽

O.J. Bjerrum

Keyword(s):

Neuropathic Pain ◽

Glutamate Uptake ◽

Glutamate Transporter ◽

Thermal Hyperalgesia ◽

Dynamic Effect ◽

Withdrawal Threshold ◽

Pain Transmission ◽

Medical Need ◽

Glutamate Transporter 1 ◽

Thermal Hypersensitivity

Abstract Introduction An unmet medical need for more effective therapies of neuropathic pain exits. Here modulation of the glutaminergic system represents an unexplored possibility. Down-regulation ofglutamate transporters potentiates pain transmission by delaying the removal of glutamate from the synapse. In the spinal cord, glutamate transporter 1 (GLT–1) is responsible for more than 90% of the glutamate uptake. Ceftriaxone, a β-lactam, is believed to induce the expression of GLT–1 through the transcriptional factor (NF-ºB) pathway, which results in induced promoter activity and thereby increased synthesis of GLT-1 protein. Objectives To evaluate the analgesic effect of ceftriaxone in the Chronic Constriction Injury (CCI) rat model of neuropathic pain and to investigate the pharmacodynamics of ceftriaxone in a chronic dosing regime. Methods In CCI rats, mechanical and thermal hypersensitivity, were determined with von Frey filaments and Hargreaves test, respectively. Groups of rats received ceftriaxone (200, 300 or 400 mg/kg, i.p.) once daily in 7–19 days and the control groups received vehicle. Results From a total of 24 CCI operated rats, 16 rats developed both mechanical (withdrawal threshold ≤3g) and thermal hypersensitivity (latency threshold ≤13 s.). Ceftriaxone alleviated mechanical allodynia and thermal hyperalgesia in CCI operated. Daily dosing of ceftriaxone 200, 300 and 400 mg/kg reached the same withdrawal threshold levels as before the CCI surgery, after 18, 12 and 7 days, respectively. This indicates that the dynamic effect of ceftriaxone is not only dependent of the dose, but also the duration of administration. Thus, it seems that dose exposure above a certain threshold is necessary to induce protein synthesis. Conclusion The CCI model is a useful model to evaluate the anti-nociceptive effects of ceftriaxone. Increased dose do not only elevate effect magnitude but also the rate of with which the effect appears.

Download Full-text

VEGF-A/VEGFR-1: a painful astrocyte-mediated signaling blocked by the anti-VEGFR-1 mAb D16F7

10.1101/2021.01.19.427244 ◽

2021 ◽

Author(s):

Laura Micheli ◽

Carmen Parisio ◽

Elena Lucarini ◽

Alessia Vona ◽

Alessandra Toti ◽

...

Keyword(s):

Neuropathic Pain ◽

Pain Treatment ◽

Electrophysiological Study ◽

Chemotherapeutic Agents ◽

Vegf Receptor ◽

Vascular Endothelial ◽

Nociceptive Neurons ◽

Medical Need ◽

Pathological Pain ◽

Endothelial Growth Factor

AbstractChemotherapy-induced neuropathic pain is a clinically relevant adverse effect of several anticancer drugs leading to dose reduction or therapy discontinuation. The lack of knowledge about the mechanisms of neuropathy development and pain chronicization makes chemotherapy-induced neuropathic pain treatment an unmet medical need. In this context, the vascular endothelial growth factor A (VEGF-A) has emerged as a neurotoxicity biomarker in a model of chemotherapy-induced neuropathy, and its decrease has been related to pain relief. Aim of this study was to clarify the VEGF-A-dependent pain signaling in the CNS for individuating new targeted therapeutic approaches. In mice, the intrathecal infusion of VEGF-A induced a dose-dependent noxious hypersensitivity mediated by the VEGF receptor 1 (VEGFR-1) as demonstrated by pharmacological and genetic tools. In electrophysiological study, VEGF-A stimulated the spinal nociceptive neurons activity through VEGFR-1. In the dorsal horn of the spinal cord, VEGF-A increased in astrocytes of animals affected by neuropathy suggesting this cell population as a source of the potent pain mediator. Accordingly, the selective knockdown of astrocytic VEGF-A, by shRNAmir, blocked the development of oxaliplatin-induced neuropathic pain. Besides, the anti-VEGFR-1 mAb D16F7 (previously described as anticancer) effectively relieved neuropathic pain induced by chemotherapeutic agents. In conclusion, astrocyte-released VEGF-A is a new player in the complex neuron-glia network that oversees physiological and pathological pain and D16F7 mAb rises as a potent pain killer strategy.

Download Full-text

Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives

Biomedicines ◽

10.3390/biomedicines9040399 ◽

2021 ◽

Vol 9 (4) ◽

pp. 399

Author(s):

Cristina Giorgio ◽

Mara Zippoli ◽

Pasquale Cocchiaro ◽

Vanessa Castelli ◽

Giustino Varrassi ◽

...

Keyword(s):

Neuropathic Pain ◽

Peripheral Neuropathy ◽

Complement System ◽

Critical Role ◽

Peripheral Neuropathies ◽

Adequate Pain Relief ◽

Medical Need ◽

New Strategy ◽

The Complement System

The complement system is a key component of innate immunity since it plays a critical role in inflammation and defense against common pathogens. However, an inappropriate activation of the complement system is involved in numerous disorders, including peripheral neuropathies. Current strategies for neuropathy-related pain fail to achieve adequate pain relief, and although several therapies are used to alleviate symptoms, approved disease-modifying treatments are unavailable. This urgent medical need is driving the development of therapeutic agents for this condition, and special emphasis is given to complement-targeting approaches. Recent evidence has underscored the importance of complement component C5a and its receptor C5aR1 in inflammatory and neuropathic pain, indicating that C5a/C5aR1 axis activation triggers a cascade of events involved in pathophysiology of peripheral neuropathy and painful neuro-inflammatory states. However, the underlying pathophysiological mechanisms of this signaling in peripheral neuropathy are not fully known. Here, we provide an overview of complement pathways and major components associated with dysregulated complement activation in peripheral neuropathy, and of drugs under development targeting the C5 system. C5/C5aR1 axis modulators could represent a new strategy to treat complement-related peripheral neuropathies. Specifically, we describe novel C5aR allosteric modulators, which may potentially become new tools in the therapeutic armory against neuropathic pain.

Download Full-text