Community Research and Development Information Service - CORDIS

FP7

NEUROPAIN Report Summary

Project ID: 602891
Funded under: FP7-HEALTH
Country: Spain

Periodic Report Summary 2 - NEUROPAIN (Neuropathic pain: biomarkers and druggable targets within the endogenous analgesia system)

Project Context and Objectives:
Neuropathic pain has a high incidence in Europe and often affects the patient’s emotional balance and quality of life. Recent meta-analyses have shown that conventional analgesic drugs are not sufficiently effective in these patients and are limited by serious side effects. The search for new analgesics is extremely difficult despite identification of several new potential targets and enormous investment by the pharmaceutical industry. Important reasons for this failure are the poor predictive validity of currently available animal models of chronic pain, which do not simulate multidimensional clinical pain, and the high inter-individual variability of neuropathic pain manifestations and treatment responses. We will overcome these obstacles by an interdisciplinary collaboration between basic science groups, clinicians and leading private companies.

The new animal model validated by the consortium is being used to evaluate the electrophysiological, behavioural, emotional and cognitive manifestations of neuropathic pain and the effectiveness of novel compounds generated by the consortium. This model, in combination with other behavioural paradigms and new conditional knockout mouse lines for specific components of the endogenous opioid and cannabinoid system, is allowing the identification of novel druggable targets and biomarkers for neuropathic pain. In this context, the three new conditional mouse lines targeting the mu and the delta opioid receptor, now available and characterised, are being employed with the new models of neuropathic pain. On the other hand, mouse lines with a conditional deletion of CB1 receptors in peripheral neurons are now available and have been evaluated for their neuropathic pain responses. Moreover, different knockout lines with conditional deletion of CB2 receptors in neurons, including nociceptive neurons, glutamatergic forebrain neurons and in descending serotoninergic neurons are now being employed in behavioural models of neuropathic pain, affective behaviours and self-medication paradigms.

Novel analgesic compounds acting on these endogenous systems developed by the private companies of the consortium will be tested in these new paradigms. Thus, the study of the in vitro pharmacological properties, the in vitro and in vivo ADME profile and the analgesic potential and suitability from the safety and toxicology point of view of novel plant-based phytocannabinoids and mu-opioid agonist/sigma-1 receptor antagonist bivalent compounds has been accomplished. Moreover, putative genetic markers of endophenotype-dependent susceptibility to neuropathic pain have been selected by means of gene expression analysis of nucleus accumbens, hippocampus and the amygdala from sham operated and neuropathic proenkephalin knockout.

Clinical studies will identify novel biomarkers for neuropathic pain using powerful genetics approaches and investigate treatment effectiveness with a translational focus based on cross validation of the findings in animals and humans. Genome-wide Analysis of migraine samples has been completed and published in Nature Genetics, and 10 of the previously reported loci were replicated. A basic ‘entry level’ set of phenotypes was identified for any genetic study of neuropathic pain. The NeuroPain Central Phenotype Database to standardizing data collection and phenotype definitions across neuropathic pain cohorts has been created and is hosted by deCODE. Moreover, neuropathic pain screening questionnaires and groups for QST (Quantitative Sensory Testing) have been defined in the QST pain research laboratory. The three clinical studies packages are progressing well, namely, the Post-menopausal surgery (PMPS) has finished recruitment, the HIV-neuropathic pain is about to doing so and the cannabinoid clinical trial has started recruitment. Dissemination activities are on course and the web page of the project is available (http://www.upf.edu/neuropain/). Six consortium meetings have already taken place, the Executive Steering Committee is in placeand an Expert External Advisory Board has been established, now with three members.
Project Results:
Objective 1 was fully accomplished in the previous reporting period. Further to what reported/delivered then (including Deliverable 1.1 and two articles), two more articles have been published (La Porta et al., Eur J Pain, 2016, Negrete et al., Neuropharmacology, 2016).
In Objective 2, mice cohorts displaying extreme phenotypes on different behavioural responses have been selected and the behavioural, emotional and cognitive consequences of neuropathic pain have been evaluated (partner 1, UPF), together with their electrophysiological correlates (partner 2, UCL). Further to what reported/delivered in the previous reporting period (including Deliverable, D2.1), a review article on neuropathic pain (Maldonado et al., 2016) has been published in Pain and a manuscript describing the results of WP2 on the evaluation of cohorts of mice displaying extreme phenotypes on different behavioural responses (Itzel-Lara et al., 2017) has been submitted to Pain, both acknowledging the support of the EC to NeuroPain.
Objective 3 is progressing well. In particular, the three new conditional mouse lines targeting the mu and the delta opioid receptor generated and characterised (partner 5, CERBM), are being employed with the new models of neuropathic pain in behavioural (partner 1, UPF) and electrophysiological (Partner 2, UCL) experiments developed in Objective 1. Partner 5 has published an article in Biological Psychiatry (Charbogne et al., 2017) on the characterization of mice lacking MOR in in GABAergic forebrain neurons. Moreover, conditional knockout animals for the preproenkephalin (Penk) gene in GABAergic forebrain neurons have been developed and are being expanded (collaboration of Partners 5 and 6) and mouse lines with a conditional deletion of CB1 receptors in peripheral neurons generated and characterised (Partner 6) are now being evaluated for their neuropathic pain responses (partner 6, UKB). The results were published in Brain Research Bulletin (Rácz et al., 2015) and Addiction Biology (Guegan et al., 2016). Moreover, different knockout lines with conditional deletion of CB2 receptors in neurons, including nociceptive neurons, glutamatergic forebrain neurons and in descending serotoninergic neurons (Syn-CB2) have also been generated (partner 6, UKB) and were investigated in behavioural models of pain, affective behaviours and self-medication paradigms (partner 1, UPF). Finally, mice with a deletion of the 2-AG producing enzyme DAGLα in nociceptive, glutamatergic forebrain and descending serotonergic neurons have been generated and characterised (Partner 6).
In Objective 4, putative genetic markers of endophenotype-dependent susceptibility to neuropathic pain have been selected by means of gene expression analysis of nucleus accumbens, hippocampus and the amygdala from sham operated and neuropathic proenkephalin knockout (PENK KO). Sciatic nerve injury affected expression of genes selected for their role in the neuronal activity (Npas4, Egr1) and opioid signalling (Pdyn and the opioid receptor Oprk1) in the amygdala and for their role in the neuronal activity (Egr1), stress (Nr3c1/gr), inflammation (IL-1beta and Aif1/Iba1) and opioid signalling (BDNF) in the hippocampus (partner 7, IF PAN). On the other hand, Partner 3 and Partner 4 have completed the study of the in vitro pharmacological properties, the in vitro and in vivo ADME profile and the analgesic potential and suitability from the safety and toxicology point of view of novel plant-based phytocannabinoids and mu-opioid agonist/sigma-1 receptor antagonist bivalent compounds, respectively, which Partners 1 and 2 are studying using their operant behavioural and electrophysiological approaches.
Objective 5 is progressing well. The completed Genome-Wide Analysis of migraine samples -the largest migraine meta-analysis to date- has been published in Nature Genetics (Partner 8) and a neuropathic pain phenotyping international consensus recommendations has been published in Pain (Partners 8 and 11). The NeuroPain Central Phenotype Database to standardizing data collection and phenotype definitions across neuropathic pain cohorts created and hosted by partner 8 (deCODE) is being extensively used within the project. Several articles on pain and several pathological conditions have also been published (Partner 8, 9 and 10). Clinical studies for the neuropathic pain study (Partner 9-Charité) have completed recruitment and re-phenotyping (N=94), for the Post-menopausal surgery (PMPS, Partner 10-HUS) have completed recruitment (N=402) and are now proceeding with re-phenotypation and QSTd (N=239) and for the HIV-1 study (POGO, Partner 11-Imperial) recruitment (N=164) and re-phenotypation, including QST (N=114) are ongoing (WP7). Genes associated with neuropathic pain syndromes (omim.org), and genes identified to harbour sequence variants associating with migraine form the list of high priority genes that Partner 8 (deCODE) routinely scans for significant associations with human NeuroPain phenotypes as they accumulate through WP7 (WP8).
Partner 9 (Charité) has started the clinical trial on the analgesic use of the phytocannabinoid compound canna¬bi¬divarin (CBDV) in patients with HIV-associated painful neuropathy within Objective 6; whilst the quantification of the degree of peripherally mediated opioid analgesia in patients receiving conventional intravenous morphine has already been completed. Those patients recruited in the clinical trial described above will be the primary target in WP10 planned studies, for which the necessary procedures have already been initiated (i.e. amendments to the ethics committee and regulatory authority).
All articles acknowledge the EC support to the NeuroPain project.

Potential Impact:
The NeuroPain project is expected to provide scientifically-sound new knowledge in the neurobiological mechanisms on how pain is generated, propagated and quenched. This proposal will deliver reliable and fully validated new animal models specifically addressing the cognitive, emotional and behavioural components of neuropathic pain as well as main side effects of treatment. This will constitute a major step forward in the preclinical research on chronic pain (WP1). Moreover, personality traits will be included in these constructs, thus allowing gaining further knowledge on interpreting patients’ responses to drug therapies (WP2). The present proposal will thus throw light on how significant inter-individual variations are relevant in the response to painful stimuli and analgesic drugs, addressing specific crucial issues such as pain predisposing genetic polymorphisms, circuitries and processes modulating nociception and endogenous analgesia, understanding the cognitive, emotional and behavioural components of pain, as well as finding out, validating and/or testing new druggable molecular targets.

Moreover, the NeuroPain project is designed towards the identification of more effective diagnostic and treatment approaches, and helping translate pre-clinical and clinical results into solutions for the benefit of the patients. Therefore, a paradigm shift in translational pain research is necessary to transform the current strategy from focusing on molecular switches of nociception to studying pain as a system-based integral response that includes psychosocial co-morbidities. The present proposal will deliver new murine models which will permit a precise evaluation of the emotional and cognitive manifestations of neuropathic pain with behavioural and electrophysiological correlates (WP1) and it will use new highly predictive behavioural models of spontaneous pain validated by partner 1 to evaluate the effectiveness of the novel cannabinoid and sigma/opioid compounds generated by partners 3 and 4. The possibility to evaluate the behavioural, emotional and cognitive manifestations of chronic pain and to characterize the spontaneous manifestations of pain in these new animal models in rodents represent an important advantage in terms of translational application of the results to humans.

The use of cannabinoids in pain relief could have limitations due to the psychoactive side effects that can be associated to these treatments. Partner 3 has currently addressed this concern by combining a psychoactive cannabinoid, delta9-tetrahydrocanbnabinol, with a non-psychoactive cannabinoid, cannabidiol in a same formulation (Sativex), which has been already approved by EMA. In addition, we will evaluate the potential for novel peripherally acting opioid drugs by quantifying the contribution of peripheral opioid receptors to the analgesic effects of systemically applied conventional opioids in clinical pain. The results can promote the development of a completely novel generation of analgesics that are devoid of side effects typical for conventional centrally acting opioids. Furthermore, an additional candidate compound acting on sigma and opioid receptors developed by partner 4 may also be tested. These two approaches are devoid of the limitations that have been raised by the use of classical cannabinoid compounds.

The NeuroPain project will also bring novel therapeutic solutions for the benefit of the patients. It is well known that treatment of chronic pain continues to be a challenge because clinical comorbidities such as depression and anxiety, rather than nociception itself, are likely to be much more influential. The present proposal will provide (1) exhaustive information about the influence of different personality traits, i.e. anxiety-like, depressive-like, social and aggressive behaviour, in neuropathic pain manifestations and (2) the samples needed for the identification of specific biomarkers (WP5). These personality traits are analogous to those evaluated in humans in WP7, facilitating the validation of results in humans (WP8). Thereafter, preclinical studies employing these new animal models will provide data with a greater assurance regarding the direction of new analgesic development, thus decreasing the timing and the economic costs needed for drug development of novel compounds against pain conditions (WP9).

List of Websites:
www.upf.edu/web/neuropain

Reported by

UNIVERSITAT POMPEU FABRA
Spain

Subjects

Life Sciences
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