Internal validity of the 9 included studies that included animal experimentation was assessed against the reporting of 5 criteria considered relevant to animal models: blinded assessment of outcome, randomisation, allocation concealment, sample size calculation, and the reporting of animal exclusions. The mean score for the selected publications was 1 out of 5. The overall reporting of quality measures for the included publications is presented in Table 6.
Large-scale expression analyses have been used to study the changes that occur under chronic pain conditions, leading to the identification of genes that function in pain signalling, some of which are yet to be fully characterised.24,100,105 The prospective significance of VGF was first derived from proteomic differential expression analysis of an in vitro model of injured sensory neurons. VGF colocalises with substance P (SP), calcitonin gene-related peptide, TrkA, and P2X3.82,83 Subsequent experiments provide the evidence for upregulation of VGF in the DRG and dorsal horn after nerve injury and inflammation.27,62,71,82,92
Acute intrathecal administration of TLQP-62 (2.5 and 5 mM) to naive rats was associated with both mechanical (von Frey filaments) and cold (cutaneous acetone) behavioural hypersensitivity.71 Similarly, intrathecal administration of both AQEE-30 and LQEQ-1982 and TLQP-2128 to naive mice, dose-dependently induced thermal hypersensitivity assessed in the warm-water tail-immersion assay.
Our understanding of pain signalling traditionally has focused on the neuronal system; however, this is neurobiologically incomplete, and immune cells have an important role as pain modulators.63,88,96 Macrophages play key roles in the complement effector functions, and the involvement of macrophages in NP pathogenesis has been well reviewed.11,16 Maratou et al.62 identified Pap/Reg2, a macrophage chemoattractant, as another molecule commonly upregulated in the 3 models of NP. Resident macrophages in the DRG proliferate after nerve injury,72 and circulating monocytes are recruited to the site of injury. Depletion of macrophages reduces mechanical hypersensitivity after nerve injury and, in an animal model of diabetic neuropathy, delays the onset and progression of pain-associated behaviours.58,67 Macrophages and monocytes express a variety of receptors, including both gC1qR and C3aR1, and activation of these receptors leads to the modulation of cytokine production and inflammatory responses.
Animal experimentation has contributed extensively to our understanding of mechanisms of disease and development of novel therapeutics; however, their predictive value of treatment effectiveness in humans remains controversial. Despite promising preclinical evidence, the lack of success in the clinic suggests that there are limitations in their translatability.77 Pain is a subjective, multifaceted symptom that can only be measured by self-reporting,102 and the presence or absence of pain in animal models cannot be directly measured and can only be inferred from the observation of surrogate behaviours.30 In the assessment of VGF-derived peptide expression, SNI is the most commonly used model (5 studies). Neuropathic pain is highly heterogeneous, both within and across underlying conditions, and the predominance of traumatic nerve injury models does not match the clinical situation.37 A more rational approach is to select models that more closely reflect the pathophysiological condition of humans. Hence, disease-specific models have been developed including models of varicella-zoster virus infection39,42,46 and HIV-associated peripheral neuropathy.103,104 To add, reflex withdrawal assessments do not necessarily measure global pain and therefore can be misleading, if not just a measure of nociception. Predictive validity may also be improved by measuring changes in behaviours that are ethologically relevant to rodents and may be affected by pain, eg, rearing,64 feeding,95 and burrowing.2
Characteristic of the field, the lack of reporting of methods undertaken to reduce the risk of bias suggests that the in vivo data reported in the studies within this review may be susceptible to bias. Experimental bias is often unintentional and can be because of low internal validity leading the scientist to incorrectly attribute an observed effect to a treatment or intervention.47 Internal validity ensures that changes observed in outcomes are due to an induced change in the independent variable rather than confounding factors. The internal validity may be compromised by a range of biases: selection, performance, detection, and attrition bias. There are several mitigations that will reduce the risk of these biases; randomisation, allocation concealment, sample size calculation, blinded assessment of outcome, and a predetermined animal eligibility criterion. Several systematic reviews and meta-analyses have provided empirical evidence highlighting that inadequate experimental approaches are associated with bias in several preclinical fields.26,48,84 Of concern is the fact that low prevalence of reporting of measures to reduce the risk of bias tend to give higher estimates of treatment effects.26,48 The introduction of the ARRIVE reporting guidelines in 201052,53,65 and the development of National Centre for the Replacement, Refinement and Reduction of Animals in Research Experimental Design Assistant gives preclinical researchers clear guidance on how to conduct animal experiments with appropriate rigour.29
In addition, as is often the case, the publications included in the review may be susceptible to publication bias. TLQP-21 is the most frequently researched VGF-derived peptide, particularly in recent years. It was not possible to estimate publication bias due to the low number of studies. However, publication bias deprives researchers of accurate data that are needed to generate new hypotheses and prevent a waste of resources in the case that a direction of research is chosen that has already been fully exploited but not published due to neutral or negative data. Thus, there is a critical and ethical need for transparency of reporting all experimental details to complete the story.90
A persistent challenge in the management of NP is to target the specific mechanisms leading to a change from normal to abnormal sensory perception while ensuring that the defensive pain perception remains intact. Targeting VGF-derived peptides may offer this opportunity. Peripheral tissue injury is associated with changes in protein expression in sensory neurons that may contribute to abnormal nociceptive processing. The publications within this review have focused on exploring the role of VGF-derived peptides in vivo but the expression of VGF in NP patients has not been characterised. The presumed abundant and selective expression of the VGF-derived peptides in blood and CSF suggest a possibility that they could be used as biomarkers of NP. The understanding of the molecular mechanisms and signalling events by which VGF-derived active peptides exert their many physiological actions is in its infancy. Future work should aim to have a better understanding of the downstream consequences of cell treatment with TLQP-21, which should uncover proteomic changes in TLQP-21-treated cells and intracellular mechanisms of TLQP-21 actions, and subsequent understanding may offer therapeutic strategies for NP. The identification of the 2 complement receptors with natural ligands, of which little is understood, suggests the possibility of a dual-ligand mechanism of action. There are both central and peripheral mechanisms to VGF-derived peptide activity; yet, it is not clear whether the mechanisms are distinct and/or have different roles in the initiation, development, and maintenance of NP. Given that VGF expression levels are very low under normal physiological conditions suggests that it does not play a role in nociception but its rapid upregulation in sensory neurons after nerve injury and inflammation along with the activation of microglia and macrophages may in part be responsible for the onset, development, and maintenance of neuropathic and inflammatory pain.
K. Okuse: an inventor on patents: Okuse K. et al. Methods of treating pain by inhibition of vgf activity EP13702262.0/WO2013 110945, and Okuse K, Ayub M, Swanwick R, et al., 2013, New receptor identified for neuropathic pain; A.S.C. Rice: reports consultancy and advisory board work for Imperial College Consultants in the last 24 months; this has included remunerated work for: Galapagos, Toray, Quartet, Lateral, Novartis, Pharmaleads, Cambridge University (Prof Peter McNaughton), Orion, Asahi Kasei, and Theranexus, outside the scope of the submitted work. In addition, A.S.C. Rice was the owner of share options in Spinifex Pharmaceuticals from which personal benefit accrued on the acquisition of Spinifex by Novartis in July 2015 and from which future milestone payments may occur. In addition, Dr Rice is named as an inventor on patents: Rice A.S.C., Vandevoorde S. and Lambert DM. Methods using N-(2-propenyl)hexadecanamide and related amides to relieve pain. WO 2005/079771, and Okuse K. et al. Methods of treating pain by inhibition of vgf activity EP13702262.0/WO2013 110945; the remaining author has nothing to declare.
The work is supported by the BBSRC (grant number BB/M011178/1).
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