Spinal neuronal activity and neuroinflammatory component in a mouse model of CFA-induced vestibulodynia.

Vestibulodynia is a complex pain disorder characterized by chronic discomfort in the vulvar region, often accompanied by tactile allodynia and spontaneous pain. In patients a depressive behaviour is also observed. In this study, we have used a model of vestibulodynia induced by complete Freund's adjuvant (CFA) focusing our investigation on the spinal cord neurons and microglia. We investigated tactile allodynia, spontaneous pain, and depressive-like behavior as key behavioral markers of vestibulodynia. In addition, we conducted in vivo electrophysiological recordings to provide, for the first time to our knowledge, the characterization of the spinal sacral neuronal activity in the L6-S1 dorsal horn of the spinal cord. Furthermore, we examined microglia activation in the L6-S1 dorsal horn using immunofluorescence, unveiling hypertrophic phenotypes indicative of neuroinflammation in the spinal cord. This represents a novel insight into the role of microglia in vestibulodynia pathology. To address the therapeutic aspect, we employed pharmacological interventions using GABApentin, amitriptyline, and PeaPol. Remarkably, all three drugs, also used in clinic, showed efficacy in alleviating tactile allodynia and depressive-like behavior. Concurrently, we also observed a normalization of the altered neuronal firing and a reduction of microglia hypertrophic phenotypes. In conclusion, our study provides a comprehensive understanding of the CFA-induced model of vestibulodynia, encompassing behavioral, neurophysiological and neuroinflammatory aspects. These data pave the way to investigate spinal cord first pain plasticity in vestibulodynia.

Complex alterations in inflammatory pain and analgesic sensitivity in young and ageing female rats: involvement of ASIC3 and Nav1.8 in primary sensory neurons.

OBJECTIVE AND DESIGN: Our aim was to determine an age-dependent role of Nav1.8 and ASIC3 in dorsal root ganglion (DRG) neurons in a rat pre-clinical model of long-term inflammatory pain. METHODS: We compared 6 and 24 months-old female Wistar rats after cutaneous inflammation. We used behavioral pain assessments over time, qPCR, quantitative immunohistochemistry, selective pharmacological manipulation, ELISA and in vitro treatment with cytokines. RESULTS: Older rats exhibited delayed recovery from mechanical allodynia and earlier onset of spontaneous pain than younger rats after inflammation. Moreover, the expression patterns of Nav1.8 and ASIC3 were time and age-dependent and ASIC3 levels remained elevated only in aged rats. In vivo, selective blockade of Nav1.8 with A803467 or of ASIC3 with APETx2 alleviated mechanical and cold allodynia and also spontaneous pain in both age groups with slightly different potency. Furthermore, in vitro IL-1ß up-regulated Nav1.8 expression in DRG neurons cultured from young but not old rats. We also found that while TNF-α up-regulated ASIC3 expression in both age groups, IL-6 and IL-1ß had this effect only on young and aged neurons, respectively. CONCLUSION: Inflammation-associated mechanical allodynia and spontaneous pain in the elderly can be more effectively treated by inhibiting ASIC3 than Nav1.8.

Electrophysiological characterization of ectopic spontaneous discharge in axotomized and intact fibers upon nerve transection: a role in spontaneous pain?

Many patients experience positive symptoms after traumatic nerve injury. Despite the increasing number of experimental studies in models of peripheral neuropathy and the knowledge acquired, most of these patients lack an effective treatment for their chronic pain. One possible explanation might be that most of the preclinical studies focused on the development of mechanical or thermal allodynia/hyperalgesia, neglecting that most of the patients with peripheral neuropathies complain mostly about spontaneous forms of pains. Here, we summarize the aberrant electrophysiological behavior of peripheral nerve fibers recorded in experimental models, the underlying pathophysiological mechanisms, and their relationship with the symptoms reported by patients. Upon nerve section, axotomized but also intact fibers develop ectopic spontaneous activity. Most interestingly, a proportion of axotomized fibers might present receptive fields in the skin far beyond the site of damage, indicative of a functional cross talk between neuromatose and intact fibers. All these features can be linked with some of the symptoms that neuropathic patients experience. Furthermore, we spotlight the consequence of primary afferents with different patterns of spontaneous discharge on the neural code and its relationship with chronic pain states. With this article, readers will be able to understand the pathophysiological mechanisms that might underlie some of the symptoms that experience neuropathic patients, with a special focus on spontaneous pain.

Fosphenytoin Alleviates Herpes Simplex Virus Infection-Induced Provoked and Spontaneous Pain-Like Behaviors in Mice.

In this study, we investigated the effects of fosphenytoin (fPHT), a water-soluble prodrug of phenytoin, on the pain responses of a mouse herpes zoster (HZ) pain model. Transdermal herpes simplex virus type 1 (HSV-1) inoculation induced mechanical allodynia and hyperalgesia of the hind paw and spontaneous pain-like behaviors, such as licking the affected skin. Intravenous injection of fPHT (15 and 30 mg/kg) alleviated HSV-1-induced provoked pain (allodynia and hyperalgesia). The suppressive effects of fPHT on provoked pain were weaker than those of diclofenac and pregabalin which were used as positive controls. fPHT, diclofenac, and pregabalin significantly suppressed HSV-1-induced spontaneous pain-like behaviors. Among them, high-dose fPHT (30 mg/kg) showed the strongest suppression. Intravenous fPHT may become a viable option for an acute HZ pain, especially for spontaneous pain.

Selective inhibition of adenylyl cyclase subtype 1 reduces inflammatory pain in chicken of gouty arthritis.

Lack of uricase leads to the high incidence of gout in humans and poultry, which is different from rodents. Therefore, chicken is considered to be one of the ideal animal models for the study of gout. Gout-related pain caused by the accumulation of urate in joints is one type of inflammatory pain, which causes damage to joint function. Our previous studies have demonstrated the crucial role of calcium-stimulated adenylyl cyclase subtype 1 (AC1) in inflammatory pain in rodents; however, there is no study in poultry. In the present study, we injected mono-sodium urate (MSU) into the left ankle joint of the chicken to establish a gouty arthritis model, and tested the effect of AC1 inhibitor NB001 on gouty arthritis in chickens. We found that MSU successfully induced spontaneous pain behaviors including sitting, standing on one leg, and limping after 1-3 h of injection into the left ankle of chickens. In addition, edema and mechanical pain hypersensitivity also occurred in the left ankle of chickens with gouty arthritis. After peroral administration of NB001 on chickens with gouty arthritis, both the spontaneous pain behaviors and the mechanical pain hypersensitivity were effectively relieved. The MSU-induced edema in the left ankle of chickens was not affected by NB001, suggesting a central effect of NB001. Our results provide a strong evidence that AC1 is involved in the regulation of inflammatory pain in poultry. A selective AC1 inhibitor NB001 produces an analgesic effect (not anti-inflammatory effect) on gouty pain and may be used for future treatment of gouty pain in both humans and poultry.

Gabapentin alleviates chronic spontaneous pain and acute hypoxia-related pain in a mouse model of sickle cell disease.

Pain is the main complication of sickle cell disease (SCD). Individuals with SCD experience acute pain episodes and chronic daily pain, both of which are managed with opioids. Opioids have deleterious side effects and use-associated stigma that make them less than ideal for SCD pain management. After recognizing the neuropathic qualities of SCD pain, clinically-approved therapies for neuropathic pain, including gabapentin, now present unique non-opioid based therapies for SCD pain management. These experiments explored the efficacy of gabapentin in relieving evoked and spontaneous chronic pain, and hypoxia/reoxygenation (H/R)-induced acute pain in mouse models of SCD. When administered following H/R, a single dose of gabapentin alleviated mechanical hypersensitivity in SCD mice by decreasing peripheral fibre activity. Gabapentin treatment also alleviated spontaneous ongoing pain in SCD mice. Longitudinal daily administration of gabapentin failed to alleviate H/R-induced pain or chronic evoked mechanical, cold or deep tissue hypersensitivity in SCD mice. Consistent with this observation, voltage-gated calcium channel (VGCC) α2 δ1 subunit expression was similar in sciatic nerve, dorsal root ganglia and lumbar spinal cord tissue from SCD and control mice. Based on these data, gabapentin may be an effective opioid alternative for the treatment of chronic spontaneous and acute H/R pain in SCD.

A deep neural network to assess spontaneous pain from mouse facial expressions.

Grimace scales quantify characteristic facial expressions associated with spontaneous pain in rodents and other mammals. However, these scales have not been widely adopted largely because of the time and effort required for highly trained humans to manually score the images. Convoluted neural networks were recently developed that distinguish individual humans and objects in images. Here, we trained one of these networks, the InceptionV3 convolutional neural net, with a large set of human-scored mouse images. Output consists of a binary pain/no-pain assessment and a confidence score. Our automated Mouse Grimace Scale integrates these two outputs and is highly accurate (94%) at assessing the presence of pain in mice across different experimental assays. In addition, we used a novel set of "pain" and "no pain" images to show that automated Mouse Grimace Scale scores are highly correlated with human scores (Pearson's r = 0.75). Moreover, the automated Mouse Grimace Scale classified a greater proportion of images as "pain" following laparotomy surgery when compared to animals receiving a sham surgery or a post-surgical analgesic. Together, these findings suggest that the automated Mouse Grimace Scale can eliminate the need for tedious human scoring of images and provide an objective and rapid way to quantify spontaneous pain and pain relief in mice.

Knowing the Neuronal Mechanism of Spontaneous Pain to Treat Chronic Pain in the Future.

Spontaneous pain is the major complain for the patients to see a doctor. Human imaging studies presented that spontaneous pain is mainly associated with activity changes in medial pain pathway, while broader brain regions were activated by allodynia pain. On behavioral level, temporally disassociation between the evoked pain and spontaneous pain was observed; these data gave a hint that the spontaneous pain and evoked pain may be mediated by different neuronal mechanisms. And more attentions should be paid to the spontaneous pain to treat the chronic pain in the future.

Intrinsic functional connectivity of insular cortex and symptoms of sickness during acute experimental inflammation.

Task-based fMRI has been used to study the effects of experimental inflammation on the human brain, but it remains unknown whether intrinsic connectivity in the brain at rest changes during a sickness response. Here, we investigated the effect of experimental inflammation on connectivity between areas relevant for monitoring of bodily states, motivation, and subjective symptoms of sickness. In a double-blind randomized controlled experiment, 52 healthy volunteers were injected with 0.6ng/kg LPS (lipopolysaccharide) or placebo, and participated in a resting state fMRI experiment after approximately 2h 45min. Resting state fMRI data were available from 48 participants, of which 28 received LPS and 20 received placebo. Bilateral anterior and bilateral posterior insula sections were used as seed regions and connectivity with bilateral orbitofrontal and cingulate (anterior and middle) cortices was investigated. Back pain, headache and global sickness increased significantly after as compared to before LPS, while a non-significant trend was shown for increased nausea. Compared to placebo, LPS was followed by increased connectivity between left anterior insula and left midcingulate cortex. This connectivity was significantly correlated to increase in back pain after LPS and tended to be related to increased global sickness, but was not related to increased headache or nausea. LPS did not affect the connectivity from other insular seeds. In conclusion, the finding of increased functional connectivity between left anterior insula and middle cingulate cortex suggests a potential neurophysiological mechanism that can be further tested to understand the subjective feeling of malaise and discomfort during a sickness response.

Endogenous adenosine A3 receptor activation selectively alleviates persistent pain states.

Chronic pain is a global burden that promotes disability and unnecessary suffering. To date, efficacious treatment of chronic pain has not been achieved. Thus, new therapeutic targets are needed. Here, we demonstrate that increasing endogenous adenosine levels through selective adenosine kinase inhibition produces powerful analgesic effects in rodent models of experimental neuropathic pain through the A3 adenosine receptor (A3AR, now known as ADORA3) signalling pathway. Similar results were obtained by the administration of a novel and highly selective A3AR agonist. These effects were prevented by blockade of spinal and supraspinal A3AR, lost in A3AR knock-out mice, and independent of opioid and endocannabinoid mechanisms. A3AR activation also relieved non-evoked spontaneous pain behaviours without promoting analgesic tolerance or inherent reward. Further examination revealed that A3AR activation reduced spinal cord pain processing by decreasing the excitability of spinal wide dynamic range neurons and producing supraspinal inhibition of spinal nociception through activation of serotonergic and noradrenergic bulbospinal circuits. Critically, engaging the A3AR mechanism did not alter nociceptive thresholds in non-neuropathy animals and therefore produced selective alleviation of persistent neuropathic pain states. These studies reveal A3AR activation by adenosine as an endogenous anti-nociceptive pathway and support the development of A3AR agonists as novel therapeutics to treat chronic pain.

TREK2 expressed selectively in IB4-binding C-fiber nociceptors hyperpolarizes their membrane potentials and limits spontaneous pain.

Ongoing/spontaneous pain behavior is associated with ongoing/spontaneous firing (SF) in adult DRG C-fiber nociceptors (Djouhri et al., 2006). Causes of this SF are not understood. We show here that conducting (sometimes called uninjured) C-nociceptors in neuropathic pain models with more hyperpolarized resting membrane potentials (Ems) have lower SF rates. Understanding the control of their Ems may therefore be important for limiting pathological pain. We report that TREK2, a leak K(+) channel, is selectively expressed in IB4 binding rat C-nociceptors. These IB4(+) C-neurons are ∼10 mV more hyperpolarized than IB4(-) C-neurons in vivo (Fang et al., 2006). TREK2 knockdown by siRNA in these neurons in culture depolarized them by ∼10 mV, suggesting that TREK2 is responsible for this ∼10 mV difference. In vivo, more hyperpolarized C-nociceptor Ems were associated with higher cytoplasmic edge-TREK2 expression (edge-TREK2). Edge-TREK2 decreased in C-neurons 7 d after axotomy, and their Ems depolarized by ∼10 mV. This again supports a contribution of TREK2 to their Ems. These relationships between (1) Em and TREK2, (2) SF rate and Em, and (3) spontaneous pain behavior and C-nociceptor SF rate suggested that TREK2 knockdown might increase spontaneous pain. After CFA-induced inflammation, spontaneous foot lifting (a measure of spontaneous pain) was (1) greater in rats with naturally lower TREK2 in ipsilateral small DRG neurons and (2) increased by siRNA-induced TREK2 knockdown in vivo. We conclude that TREK2 hyperpolarizes IB4 binding C-nociceptors and limits pathological spontaneous pain. Similar TREK2 distributions in small DRG neurons of several species suggest that these role(s) of TREK2 may be widespread.

Studying ongoing and spontaneous pain in rodents--challenges and opportunities.

The measurement of spontaneous ongoing pain in rodents is a multiplex issue and a subject of extensive and longstanding debate. Considering the need to align available rodent models with clinically relevant forms of pain, it is of prime importance to thoroughly characterize behavioral outcomes in rodents using a portfolio of measurements that are not only stimulus-dependent but also encompass voluntary behavior in unrestrained animals. Moreover, the temporal course and duration of behavioral tests should be taken into consideration when we plan our studies to measure explicit chronic pain, with a particular emphasis on performing longitudinal studies in rodents. While using rodents as model organisms, it is also worth considering their circadian rhythm and the influence of the test conditions on the behavioral results, which are affected by social paradigms, stress and anxiety. In humans, general wellbeing is closely related to pain perception, which also makes it necessary in rodents to consider modulators as well as readouts of overall wellbeing. Optimizing the above parameters in study design and the new developments that are forthcoming to test the affective motivational components of pain hold promise in solving inconsistencies across studies and improving their broad applicability in translational research. In this review, we critically discuss a variety of behavioral tests that have been developed and reported in recent years, attempt to weigh their benefits and potential limitations, and discuss key requirements and challenges that lie ahead in measuring ongoing pain in rodent models.

Strategies for measuring non-evoked pain in preclinical models of neuropathic pain: Systematic review.

The development of new analgesics for neuropathic pain treatment is crucial. The failure of promising drugs in clinical trials may be related to the over-reliance on reflex-based responses (evoked pain) in preclinical drug testing, which may not fully represent clinical neuropathic pain, characterized by spontaneous non-evoked pain (NEP). Hence, strategies for assessing NEP in preclinical studies emerged. This systematic review identified 443 articles evaluating NEP in neuropathic pain models (mainly traumatic nerve injuries in male rodents). An exponential growth in NEP evaluation was observed, which was assessed using 48 different tests classified in 12 NEP-related outcomes: anxiety, exploration/locomotion, paw lifting, depression, conditioned place preference, gait, autotomy, wellbeing, facial grooming, cognitive impairment, facial pain expressions and vocalizations. Although most of these outcomes showed clear limitations, our analysis suggests that conditioning-associated outcomes, pain-related comorbidities, and gait evaluation may be the most effective strategies. Moreover, a minimal part of the studies evaluated standard analgesics. The greater emphasis on evaluating NEP aligning with clinical pain symptoms may enhance analgesic drug development, improving clinical translation.

Spinal nerve ligation: An experimental model to study neuropathic pain in rats and mice.

Neuropathic pain, defined as the most terrible of all tortures, which a nerve wound may inflict, is a common chronic painful condition caused by gradual damage or dysfunction of the somatosensory nervous system. As with many chronic diseases, neuropathic pain has a profound economic and emotional impact worldwide and represents a major public health issue from a treatment standpoint. This condition involves multiple sensory symptoms including impaired transmission and perception of noxious stimuli, burning, shooting, spontaneous pain, mechanical or thermal allodynia and hyperalgesia. Current pharmacological options for the treatment of neuropathic pain are limited, ineffective and have unacceptable side effects. In this framework, a deeper understanding of the pathophysiology and molecular mechanisms associated with neuropathic pain is key to the development of promising new therapeutical approaches. For this purpose, a plethora of experimental models that mimic common clinical features of human neuropathic pain have been characterized in rodents, with the spinal nerve ligation (SNL) model being one of the most widely used. In this chapter, we provide a detailed surgical procedure of the SNL model used to induce neuropathic pain in rats and mice. We further describe the behavioral approaches used for stimulus-evoked and spontaneous pain assessment in rodents. Finally, we demonstrate that our SNL model induces multiple pain behaviors in rats and mice.

Machine learning-based evaluation of spontaneous pain and analgesics from cellular calcium signals in the mouse primary somatosensory cortex using explainable features.

Introduction: Pain that arises spontaneously is considered more clinically relevant than pain evoked by external stimuli. However, measuring spontaneous pain in animal models in preclinical studies is challenging due to methodological limitations. To address this issue, recently we developed a deep learning (DL) model to assess spontaneous pain using cellular calcium signals of the primary somatosensory cortex (S1) in awake head-fixed mice. However, DL operate like a "black box", where their decision-making process is not transparent and is difficult to understand, which is especially evident when our DL model classifies different states of pain based on cellular calcium signals. In this study, we introduce a novel machine learning (ML) model that utilizes features that were manually extracted from S1 calcium signals, including the dynamic changes in calcium levels and the cell-to-cell activity correlations. Method: We focused on observing neural activity patterns in the primary somatosensory cortex (S1) of mice using two-photon calcium imaging after injecting a calcium indicator (GCaMP6s) into the S1 cortex neurons. We extracted features related to the ratio of up and down-regulated cells in calcium activity and the correlation level of activity between cells as input data for the ML model. The ML model was validated using a Leave-One-Subject-Out Cross-Validation approach to distinguish between non-pain, pain, and drug-induced analgesic states. Results and discussion: The ML model was designed to classify data into three distinct categories: non-pain, pain, and drug-induced analgesic states. Its versatility was demonstrated by successfully classifying different states across various pain models, including inflammatory and neuropathic pain, as well as confirming its utility in identifying the analgesic effects of drugs like ketoprofen, morphine, and the efficacy of magnolin, a candidate analgesic compound. In conclusion, our ML model surpasses the limitations of previous DL approaches by leveraging manually extracted features. This not only clarifies the decision-making process of the ML model but also yields insights into neuronal activity patterns associated with pain, facilitating preclinical studies of analgesics with higher potential for clinical translation.

Analgesia of noninvasive electrical stimulation of the dorsolateral prefrontal cortex: A systematic review and meta-analysis.

OBJECTIVE: The dorsolateral prefrontal cortex (DLPFC) is implicated in pain modulation, suggesting its potential as a therapeutic target for pain relief. However, studies on transcranial electrical stimulation (tES) over the DLPFC yielded diverse results, likely due to differences in stimulation protocols or pain assessment methods. This study aims to evaluate the analgesic effects of DLPFC-tES using a meta-analytical approach. METHODS: A meta-analysis of 29 studies involving 785 participants was conducted. The effects of genuine and sham DLPFC-tES on pain perception were examined in healthy individuals and patients with clinical pain. Subgroup analyses explored the impact of stimulation parameters and pain modalities. RESULTS: DLPFC-tES did not significantly affect pain outcomes in healthy populations but showed promise in reducing pain-intensity ratings in patients with clinical pain (Hedges' g = -0.78, 95% CI = [-1.33, -0.24], p = 0.005). Electrode placement significantly influenced the analgesic effect, with better results observed when the anode was at F3 and the cathode at F4. CONCLUSIONS: DLPFC-tES holds potential as a cost-effective pain management option, particularly for clinical populations. Optimizing electrode placement, especially with an symmetrical configuration, may enhance therapeutic efficacy. These findings underscore the promise of DLPFC-tES for alleviating perceived pain intensity in clinical settings, emphasizing the importance of electrode placement optimization.

Hydralazine plays an immunomodulation role of pro-regeneration in a mouse model of spinal cord injury.

Spinal cord injury (SCI) results in severe motor and sensory dysfunction with no effective therapy. Spinal cord debris (sp) from injured spinal cord evokes secondary SCI continuously. We and other researchers have previously clarified that it is mainly bone marrow derived macrophages (BMDMs) infiltrating in the lesion epicenter to clear sp, rather than local microglia. Unfortunately, the pro-inflammatory phenotype of these infiltrating BMDMs is predominant which impairs wound healing. Hydralazine, as a potent vasodilator and scavenger of acrolein, has protective effects in many diseases. Hydralazine is also confirmed to promote motor function and hypersensitivity in SCI rats through scavenging acrolein. However, few studies have explored the effects of hydralazine on immunomodulation, as well as spontaneous pain and emotional response, the important syndromes in clinical patients. It remains unclear whether hydralazine affects infiltrating BMDMs after SCI. In this study, we targeted BMDMs to explore the influence of hydralazine on immune cells in a mouse model of SCI, and also investigated the contribution of polarized BMDMs to hydralazine-induced neurological function recovery after SCI in male mice. The adult male mice underwent T10 spinal cord compression. The results showed that in addition to improving motor function and hypersensitivity, hydralazine relieved SCI-induced spontaneous pain and emotional response, which is a newly discovered function of hydralazine. Hydralazine inhibited the recruitments of pro-inflammatory BMDMs and educated infiltrated BMDMs to a more reparative phenotype involving in multiple biological processes associated with SCI pathology, including immune/inflammation response, neurogenesis, lipid metabolism, oxidative stress, fibrosis formation, and angiogenesis, etc. As an overall effect, hydralazine-treated BMDMs loaden with sp partially rescued neurological function after SCI. It is concluded that hydralazine plays an immunomodulation role of educating pro-inflammatory BMDMs to a more reparative phenotype; and hydralazine-educated BMDMs contribute to hydralazine-induced improvement of neurological function in SCI mice, which provides support for drug and cell treatment options for SCI therapy.

Assessing Orofacial Pain Behaviors in Animal Models: A Review.

Orofacial pain refers to pain occurring in the head and face, which is highly prevalent and represents a challenge to clinicians, but its underlying mechanisms are not fully understood, and more studies using animal models are urgently needed. Currently, there are different assessment methods for analyzing orofacial pain behaviors in animal models. In order to minimize the number of animals used and maximize animal welfare, selecting appropriate assessment methods can avoid repeated testing and improve the reliability and accuracy of research data. Here, we summarize different methods for assessing spontaneous pain, evoked pain, and relevant accompanying dysfunction, and discuss their advantages and disadvantages. While the behaviors of orofacial pain in rodents are not exactly equivalent to the symptoms displayed in patients with orofacial pain, animal models and pain behavioral assessments have advanced our understanding of the pathogenesis of such pain.

Neuropathic pain changes the output of rat lamina I spino-parabrachial neurons.

• Spared nerve injury (SNI) altered the action potential (AP) output of lamina I spino-parabrachial neurons (SPNs) without affecting their resting potential or membrane resistance. • In one-third of SPNs, high-threshold dorsal root stimulation elicited persistent AP firing which was never observed in cells from naïve animals. • 38% of SPNs from SNI rats showed spontaneous persistent AP firing. • After SNI low- and high-output SPNs were no longer nociceptive-specific as part of them responded with APs to low-threshold stimulation. • These SNI-induced changes of SPN output might represent cellular mechanisms for neuropathy-associated allodynia, hyperalgesia, and spontaneous pain.

Human experimental pain models: A review of standardized methods in drug development.

Human experimental pain models are essential in understanding the pain mechanisms and appear to be ideally suited to test analgesic compounds. The challenge that confronts both the clinician and the scientist is to match specific treatments to different pain-generating mechanisms and hence reach a pain treatment tailored to each individual patient. Experimental pain models offer the possibility to explore the pain system under controlled settings. Standardized stimuli of different modalities (i.e., mechanical, thermal, electrical, or chemical) can be applied to the skin, muscles, and viscera for a differentiated and comprehensive assessment of various pain pathways and mechanisms. Using a multimodel-multistructure testing, the nociception arising from different body structures can be explored and modulation of specific biomarkers by new and existing analgesic drugs can be profiled. The value of human experimental pain models is to link animal and clinical pain studies, providing new possibilities for designing successful clinical trials. Spontaneous pain, the main compliant of the neuropathic patients, but currently there is no human model available that would mimic chronic pain. Therefore, current human pain models cannot replace patient studies for studying efficacy of analgesic compounds, although being helpful for proof-of-concept studies and dose finding.