The Fibromyalgia Pain Experience: A Scoping Review of the Preclinical Evidence for Replication and Treatment of the Affective and Cognitive Pain Dimensions.

Fibromyalgia is a chronic, widespread pain disorder that is strongly represented across the affective and cognitive dimensions of pain, given that the underlying pathophysiology of the disorder is yet to be identified. These affective and cognitive deficits are crucial to understanding and treating the fibromyalgia pain experience as a whole but replicating this multidimensionality on a preclinical level is challenging. To understand the underlying mechanisms, animal models are used. In this scoping review, we evaluate the current primary animal models of fibromyalgia regarding their translational relevance within the affective and cognitive pain realms, as well as summarize treatments that have been identified preclinically for attenuating these deficits.

The role of the male rat infralimbic cortex in distraction analgesia.

Cognitive interventions, including distraction, have been successfully utilized in the manipulation of experimental pain and the treatment of clinical pain. Attentional diversions can reduce the experience of pain, a phenomenon known as distraction analgesia (DA). Prior research has suggested that variations in stimulus intensity may influence the magnitude of DA. However, the neural substrates of DA remain largely unknown. Converging evidence suggests that the infralimbic cortex (IL) in the brains of rats may contribute to the phenomenon of DA. The function of the rat IL in DA has never been directly investigated, therefore, this study sought to identify the role of the IL at two levels of noxious stimulus intensity among brain-intact and IL lesioned male rats within an established rat model of DA. A distractor object reduced formalin-induced nociceptive behavior in brain-intact rats, and this DA effect was detectable during low- (0.5% formalin) and high-intensity (1% formalin) stimulation. IL lesion resulted in a near-complete elimination of the DA effect and an overall reduction in formalin pain. These results provide the first known evidence that (i) the IL is involved in processing DA in rats, (ii) the IL contributes to formalin-induced nociceptive behavior irrespective of distraction, and (iii) a high-intensity stimulation was generally more susceptible to DA than low-intensity stimulation. These findings may further inform the mechanisms and future development of non-pharmacological strategies to reduce pain.

Pregabalin and hyperbaric oxygen therapy on pain thresholds and anxio-depressive behaviors in a preclinical fibromyalgia pain model.

Fibromyalgia (FM) is a chronic, widespread pain disorder generally of a non-inflammatory nature with many known affective and cognitive comorbidities. There is promise in the implementation of hyperbaric oxygen therapy (HBO2) for alleviating FM pain and comorbidities, despite no work investigating the efficacy of this treatment in prominent preclinical FM models. This project aimed to investigate the affective components, specifically anhedonia and anxiety, associated with an acidic saline model of FM in rats. We investigated the acidic saline model's ability to produce the sensory component of FM through reduced mechanical thresholds, as well as anxiety-like and avoidance behaviors through measures of open field and place escape/avoidance. We further investigated the use of pregabalin, a known FM therapeutic agent, in reducing negative sensory and affective measures within the model. Results revealed insignificant between-group differences for measures of anxiety, despite animals in the FM condition showing significantly reduced mechanical thresholds. Results further revealed that the acidic saline model was effective in increasing place escape/avoidance behavior among animals in the FM condition, with pregabalin reducing avoidance behaviors. In addition, we investigated the role of HBO2 [two 60-minute treatments at 2.0 ATA (atmospheres absolute)] in alleviating FM-like pain, anxiety, and anhedonia in the acidic saline model, utilizing mechanical paw withdrawal thresholds, open field, and sucrose preference measures. Results revealed that the acidic saline model produced reduced thresholds indicative of FM-like pain. Data did not provide support for the presence of anxio-depressive comorbidities associated with the FM model. HBO2 treatment did not significantly increase mechanical thresholds as expected. Future studies should seek to investigate the experimental circumstances within which the acidic saline model produces negative affect alongside hyperalgesia in order to contribute to the development of a multidimensional FM treatment methodology.

Evaluating the impact of age and inflammatory duration on behavioral assessments of nociception.

Pain is a prevalent issue for elderly individuals. Unfortunately, it remains unclear how acute and chronic pain differs as a function of age, and surprisingly, there is even disagreement on how the sensory and affective dimensions of pain change with age. Therefore, the current investigation evaluated such age differences with behavioral methodology using a preclinical model of arthritis. The primary factors of interest were age and chronicity of pain using behavioral assessments designed to measure sensory and affective dimensions of pain processing. Mechanical and thermal paw withdrawal thresholds demonstrated unique outcomes associated with sensory processing across age. The processing of pain affect measured by the Place Escape/Avoidance Paradigm (PEAP testing) also demonstrated age related effects. Overall, younger animals appeared more sensitive to nociceptive stimuli than older animals. However, the results from the current study suggest that chronicity of pain can be impactful for how older animals process pain related affect and avoidance. The finding of unique patterns of pain across age and duration of pain highlights the clinical literature. Future research should aim to elucidate mechanisms for affective processing of chronic pain in older subjects.

The Use of an FR1 Schedule Operant Approach-Avoidance Paradigm to Measure the Aversiveness of Neuropathic and Inflammatory Pain.

Pain is a subjective, private, yet universal phenomenon that depends on a unique combination of sensory, affective, and evaluative characteristics. Although preclinical models have been used to understand much of pain physiology, the inability to communicate with animals limits affective and evaluative feedback and has constrained traditional behavioral methods to adequately represent and study the multidimensional pain experience. Therefore, this study sought to characterize the affective component of pain within a novel operant approach-avoidance paradigm (AAP) to determine which type of pain (inflammatory and neuropathic) may be more aversive. To reveal the possible differences in pain aversiveness within the AAP paradigm, animals received bilateral inflammatory and neuropathic pain conditions and were given the choice to a) forgo appetitive reward by not receiving noxious stimulus of either inflammatory or neuropathic conditions or b) receive noxious stimulus in exchange for an appetitive reward. Although all pain conditions produced significant hypersensitivity, the AAP results revealed there was no preference in the stimulation of a specific paw in the bilateral pain conditions. The finding suggests that despite unique clinical pain characteristics for inflammatory and neuropathic conditions, the lack of observable differences in the pain conditions may not necessarily equate to the overall similarity in aversiveness, but rather that the fixed ratio (FR1) paradigm presentation allowed appetitive reward to be more salient, highlighting the complexities of competing motivational drives of pain and hunger when satiating hunger is always guaranteed. Thus, future studies should seek to further tease apart this relationship with a different schedule and food-controlled methodologies. The development of such preclinical approaches can thoroughly investigate the intricacy of competing drives and likely reveal important information regarding the complexity of pain, enhancing our understanding of pain perception in individuals suffering from comorbid pain states.

Recurrent Hypoglycemia Exacerbates Cerebral Ischemic Damage in Diabetic Rats via Enhanced Post-Ischemic Mitochondrial Dysfunction.

Diabetes significantly increases the risk of stroke and post-stroke mortality. Recurrent hypoglycemia (RH) is common among diabetes patients owing to glucose-lowering therapies. Earlier, we showed that RH in a rat model of insulin-dependent diabetes exacerbates cerebral ischemic damage. Impaired mitochondrial function has been implicated as a central player in the development of cerebral ischemic damage. Hypoglycemia is also known to affect mitochondrial functioning. The present study tested the hypothesis that prior exposure of insulin-treated diabetic (ITD) rats to RH exacerbates brain damage via enhanced post-ischemic mitochondrial dysfunction. In a rat model of streptozotocin-induced diabetes, we evaluated post-ischemic mitochondrial function in RH-exposed ITD rats. Rats were exposed to five episodes of moderate hypoglycemia prior to the induction of cerebral ischemia. We also evaluated the impact of RH, both alone and in combination with cerebral ischemia, on cognitive function using the Barnes circular platform maze test. We observed that RH exposure to ITD rats leads to increased cerebral ischemic damage and decreased mitochondrial complex I activity. Exposure of ITD rats to RH impaired spatial learning and memory. Our results demonstrate that RH exposure to ITD rats potentially increases post-ischemic damage via enhanced post-ischemic mitochondrial dysfunction.

A model of pain behaviors in freely moving rats generated by controllable electrical stimulation of the peripheral nerve.

BACKGROUND: Neuropathic pain patients have described experiencing unprovoked, intermittent pain attacks with shooting, stabbing, and burning qualities. Rodent models used in previous literature usually only involve acute exposure, and/or are unable to manipulate the stimulation intensity in vivo by the experimenter during an experiment. NEW METHOD: This paper describes a method to induce controllable pain behaviors in rodents using a wireless portable electronic device that can be manipulated within the course of an experiment. A stimulating electrode was implanted at the L5 spinal nerve location in Sprague-Dawley rats and our custom-built wireless stimulating device was attached to deliver variable stimulation in freely moving animals (50 Hz, 0.5 V; 100 Hz, 1 V). RESULTS: Implantation itself did not induce hypersensitivity as measured by the mechanical paw withdrawal threshold test. Observation of pain behaviors (paw elevation and licking) indicated that high stimulation intensity yielded a significant increase in pain behaviors. Even further, high intensity stimulation resulted in a behavioral "wind-up" of pain behaviors that persisted into the resting period when no stimulation was applied. COMPARISON WITH EXISTING METHODS AND CONCLUSIONS: This method can be used to study pain behaviors in a controllable way in freely moving rodents in comparison to existing models that are acute and/or are unable to manipulate the stimulation intensity in vivo.

Assessing the aversive nature of pain with an operant approach/avoidance paradigm.

Preclinical pain assessments can be criticized for failing to adequately characterize the human clinical pain experience. Although recent assessments have improved upon this shortcoming, there are still significant limitations. One concern is that current procedures fail to examine underlying motivational drives related to pain. Therefore, we used a novel approach-avoidance paradigm that allowed a rat to either satisfy hunger or avoid noxious stimulation to reveal prioritizing of motivational drives. The operant paradigm utilized a single lever that the animal pressed for appetitive reward (approach). The lever press was associated with mechanical stimulation of an inflamed paw induced by subcutaneous injection of carrageenan (avoidance). The results revealed that carrageenan-injected animals had a significant suppression of lever pressing and, in addition, had a longer latency to approach and press a lever for appetitive reward. The pattern of operant behavioral responses indicates that the motivation to avoid pain superseded the motivation to alleviate hunger. Utilization of approach-avoidance paradigms, such as this one, can allow researchers to unravel the complexities of the pain experience with the goal of enhancing translation to clinical efficacy.

Minocycline inhibits neurogenic inflammation by blocking the effects of tumor necrosis factor-α.

It has been well established that neurogenic inflammation is one of the major pathological processes underlying inflammatory pain, but there are few effective anti-inflammatory drugs to alleviate such pain. The present study shows that minocycline, a widely used glial activation inhibitor, is effective in reducing neurogenic inflammation. Patch-clamp recordings showed that small sized dorsal root ganglion (DRG) neurons were dramatically excited following intradermal capsaicin injection in the rat hind paw, evidenced by decreased rheobase and membrane threshold. Pretreatment with minocycline (30 mg/kg for 1 day, intraperitoneal injection) blocked the increased neuronal excitability. Western blot and immunostaining of DRG revealed the activation of satellite glial cells (SGCs) following capsaicin injection. The up-regulation of glial fibrillary acidic protein (GFAP) was significantly inhibited by minocycline pre-administration. Measurement of tumor necrosis factor α (TNF-α) and its receptor, TNF-α receptor 1 (TNFR1), showed that minocycline mainly blocked the up-regulation of TNF-α in SGCs and TNFR1s in neurons following capsaicin injection. The pivotal role of TNF-α in neurogenic inflammation was further supported by the findings that incubation DRG with TNF-α mimicked the increased excitability of DRG neurons induced by capsaicin injection, and that TNF-α application enhanced cutaneous vasodilation in the hind paws induced by antidromic electrical stimulation of dorsal roots. Based on these results, we propose that minocycline is a potential therapeutic drug that can reduce neuronal excitability and neurogenic inflammation by working on SGCs to inhibit the expression of TNF-α.

Disruption of neurogenesis and cortical development in transgenic mice misexpressing Olig2, a gene in the Down syndrome critical region.

The basic helix-loop-helix (bHLH) transcription factor Olig2 is crucial for mammalian central nervous system development. Human ortholog OLIG2 is located in the Down syndrome critical region in trisomy 21. To investigate the effect of Olig2 misexpression on brain development, we generated a developmentally regulated Olig2-overexpressing transgenic line with a Cre/loxP system. The transgenic mice with Olig2 misexpression in cortical neural stem/progenitor cells exhibited microcephaly, cortical dyslamination, hippocampus malformation, and profound motor deficits. Ectopic misexpression of Olig2 impaired cortical progenitor proliferation and caused precocious cell cycle exit. Massive neuronal cell death was detected in the developing cortex of Olig2-misexpressing mice. In addition, Olig2 misexpression led to a significant downregulation of neuronal specification factors including Ngn1, Ngn2 and Pax6, and a defect in cortical neurogenesis. Chromatin-immunoprecipitation and sequencing (ChIP-Seq) analysis indicates that Olig2 directly targets the promoter and/or enhancer regions of Nfatc4, Dscr1/Rcan1 and Dyrk1a, the critical neurogenic genes that contribute to Down syndrome phenotypes, and inhibits their expression. Together, our study suggests that Olig2 misexpression in neural stem cells elicits neurogenesis defects and neuronal cell death, which may contribute to developmental disorders including Down syndrome, where OLIG2 is triplicated on chromosomal 21.

Pain inhibition by optogenetic activation of specific anterior cingulate cortical neurons.

Cumulative evidence from both humans and animals suggests that the anterior cingulate cortex (ACC) is important for pain-related perception, and thus a likely target for pain relief therapy. However, use of existing electrode based ACC stimulation has not significantly reduced pain, at least in part due to the lack of specificity and likely co-activation of both excitatory and inhibitory neurons. Herein, we report a dramatic reduction of pain behavior in transgenic mice by optogenetic stimulation of the inhibitory neural circuitry of the ACC expressing channelrhodopsin-2. Electrophysiological measurements confirmed that stimulation of ACC inhibitory neurons is associated with decreased neural activity in the ACC. Further, a distinct optogenetic stimulation intensity and frequency-dependent inhibition of spiking activity in the ACC was observed. Moreover, we confirmed specific electrophysiological responses from different neuronal units in the thalamus, in response to particular types of painful stimuli (i,e., formalin injection, pinch), which we found to be modulated by optogenetic control of the ACC inhibitory neurons. These results underscore the inhibition of the ACC as a clinical alternative in inhibiting chronic pain, and leads to a better understanding of the pain processing circuitry of the cingulate cortex.

Behavioral neuroscience of psychological pain.

Pain is a common word used to refer to a wide range of physical and mental states sharing hedonic aversive value. Three types of pain are distinguished in this article: Physical pain, an aversive state related to actual or potential injury and disease; social pain, an aversive emotion associated to social exclusion; and psychological pain, a negative emotion induced by incentive loss. This review centers on psychological pain as studied in nonhuman animals. After covering issues of terminology, the article briefly discusses the daily-life significance of psychological pain and then centers on a discussion of the results originating from two procedures involving incentive loss: successive negative contrast-the unexpected devaluation of a reward-and appetitive extinction-the unexpected omission of a reward. The evidence reviewed points to substantial commonalities, but also some differences and interactions between physical and psychological pains. This evidence is discussed in relation to behavioral, pharmacological, neurobiological, and genetic factors that contribute to the multidimensional experience of psychological pain.

The elusive rat model of conditioned placebo analgesia.

Recent research on human placebo analgesia has suggested the need for rodent models to further elucidate the neural substrates of the placebo effect. This series of 3 experiments therefore was performed in an attempt to develop a model of placebo analgesia in rats. In each study, female Sprague-Dawley rats received an L5 spinal nerve ligation to induce a neuropathic pain condition. Each rat then underwent a 4-day conditioning procedure in which an active analgesic drug or its vehicle (unconditioned stimulus) was associated with the following cues (conditioned stimuli): novel testing room (environmental), vanilla scent cue (olfactory), dim incandescent lighting (visual), restraint procedure/injection (tactile), and time of day and injection-test latency (temporal). The analgesics for each experiment were as follows: Experiment 1 used 90 mg/kg gabapentin, experiment 2 used 3mg/kg loperamide hydrochloride, and experiment 3 used 6 mg/kg morphine sulfate. On the following test day, half of the animals received the opposite treatment, resulting in 4 conditioning manipulations: drug/drug, drug/vehicle, vehicle/drug, and vehicle/vehicle. Nociceptive thresholds were assessed with the mechanical paw withdrawal threshold test each day after the conditioning procedure. In all 3 experiments, no significant differences were detected on test day between control and placebo groups, indicating a lack of a conditioned placebo analgesic response. Our results contrast with prior research that implies the existence of a reliable and robust response to placebo treatment. We conclude that placebo analgesia in rats is not particularly robust and that it is difficult to achieve using conventional procedures and proper experimental design.

The anterior cingulate cortex and pain processing.

The neural network that contributes to the suffering which accompanies persistent pain states involves a number of brain regions. Of primary interest is the contribution of the cingulate cortex in processing the affective component of pain. The purpose of this review is to summarize recent data obtained using novel behavioral paradigms in animals based on measuring escape and/or avoidance of a noxious stimulus. These paradigms have successfully been used to study the nature of the neuroanatomical and neurochemical contributions of the anterior cingulate cortex (ACC) to higher order pain processing in rodents.

An overview of animal models of pain: disease models and outcome measures.

UNLABELLED: Pain is ultimately a perceptual phenomenon. It is built from information gathered by specialized pain receptors in tissue, modified by spinal and supraspinal mechanisms, and integrated into a discrete sensory experience with an emotional valence in the brain. Because of this, studying intact animals allows the multidimensional nature of pain to be examined. A number of animal models have been developed, reflecting observations that pain phenotypes are mediated by distinct mechanisms. Animal models of pain are designed to mimic distinct clinical diseases to better evaluate underlying mechanisms and potential treatments. Outcome measures are designed to measure multiple parts of the pain experience, including reflexive hyperalgesia measures, sensory and affective dimensions of pain, and impact of pain on function and quality of life. In this review, we discuss the common methods used for inducing each of the pain phenotypes related to clinical pain syndromes as well as the main behavioral tests for assessing pain in each model. PERSPECTIVE: Understanding animal models and outcome measures in animals will assist in translating data from basic science to the clinic.

Role of the ventrolateral orbital cortex and medial prefrontal cortex in incentive downshift situations.

The present research evaluated the role of two prefrontal cortex areas, the ventrolateral orbital cortex (VLO) and the medial prefrontal cortex (mPFC), on two situations involving incentive downshifts, consummatory successive negative contrast (cSNC) with sucrose solutions and Pavlovian autoshaping following continuous vs. partial reinforcement with food pellets. Animals received electrolytic lesions and then were tested on cSNC, autoshaping, open-field activity, and sucrose sensitivity. Lesions of the VLO reduced suppression of consummatory behavior after the incentive downshift, but only during the first downshift trial, and also eliminated the enhancement of anticipatory behavior during partial reinforcement, relative to continuous reinforcement, in autoshaping. There was no evidence of specific effects of mPFC lesions on incentive downshifts. Open-field activity was also reduced by VLO lesions, but only in the central area, whereas mPFC lesions had no observable effects on activity. Animals with mPFC lesions exhibited decreased consumption of the lowest sucrose concentration, whereas no effects were observed in animals with VLO lesions. These results suggest that the VLO may exert nonassociative (i.e., motivational, emotional) influences on behavior in situations involving incentive downshifts. No clear role on incentive downshift was revealed by mPFC lesions.

The place escape/avoidance paradigm: a novel method to assess nociceptive processing.

This paper summarizes a behavioral paradigm that was developed as a novel method to dissociate the multidimensional pain experience in rodents. The place escape/avoidance paradigm (PEAP) is based on the assumption that if animals escape and/or avoid a noxious stimulus, then the stimulus is aversive to the animal. Data is presented showing that when animals are placed in a specific environmental condition, they will perform purposeful behavior to escape and/or avoid the noxious stimulus. Additional data is presented to demonstrate the validity of the behavioral paradigm and how the paradigm has been used to test the hypothesis that the affective/motivational dimension of pain can be dissociated and studied independent of sensory pain processing. The behavioral paradigm highlights the emerging trend in the area of pain research and management towards developing more realistic behavioral paradigms to assess nociceptive processing in rodent models of chronic pain.

Pain affect in the absence of pain sensation: evidence of asomaesthesia after somatosensory cortex lesions in the rat.

Multidimensional models of pain processing distinguish the sensory, motivational, and affective components of the pain experience. Efforts to understand underlying mechanisms have focused on isolating the roles of specific brain structures, including both limbic and non-limbic cortical areas, in the processing of nociceptive stimuli. The purpose of this study was to examine the role of the somatosensory cortex in both sensory and affective aspects of pain processing. It was hypothesized that animals with lesions of the hind limb area of the somatosensory cortex would demonstrate altered sensory processing (asomaesthesia, a deficit in the ability to detect and identify somatic sensation) in the presence of an inflammatory state when compared to animals with sham lesions. The level of pain affect produced by an inflammatory pain condition was not expected to change, as this region has not demonstrated a role in processing the affective component of pain. Seventy-nine adult female Sprague-Dawley rats were randomly assigned to receive bilateral lesions or a sham procedure. The results showed that somatosensory lesions to the hindlimb region altered responses to mechanical stimulation in the presence of experimentally-induced inflammation, but did not attenuate the inflammation-induced paw volume changes or the level of pain affect, as demonstrated by escape/avoidance behavior in response to mechanical stimulation. Overall, these results support previous evidence suggesting that the somatosensory cortex is primarily involved in the processing the sensory/discriminative aspect of pain, and the current study is the first to demonstrate the presence of pain affect in the absence of somatosensory processing.

Evaluating underlying neuronal activity associated with escape/avoidance behavior in response to noxious stimulation in adult rats.

The place escape/avoidance paradigm (PEAP) is a behavioral test designed to quantify the level of unpleasantness evoked by painful stimuli by assessing the willingness of a subject to escape/avoid a preferred area when it is associated with noxious stimulation. Previous studies have demonstrated that escape/avoidance behavior is dependent on activity in the anterior cingulate cortex (ACC), a region of the limbic system involved in processing the emotional component of pain in humans and animals. Analysis of c-Fos expression in the ACC confirmed that the escape/avoidance response to noxious stimuli corresponds to changes in neural activation in this region. Behavioral tests such as the PEAP may be more sensitive to changes in supraspinal pain processing and could contribute to the development of novel analgesics in the future.

Impairment of recovery from incentive downshift after lesions of the anterior cingulate cortex: emotional or cognitive deficits?

The anterior cinculate cortex (ACC) is known to be implicated in pain-fear and reward expectations. Animals were given electrolytic lesions of the ACC and then trained in the consummatory successive negative contrast (cSNC) situation. In cSNC, animals exposed to an incentive downshift from 32% to 4% sucrose exhibit less consummatory behavior than animals always exposed to 4% sucrose. The ACC lesion had no measurable effects on the consummatory performance of animals before the downshift (i.e., the lesion did not affect consumption of 32% vs. 4% sucrose); on the performance of unshifted, 4% sucrose animals; and on the first downshift trial. However, ACC animals exhibited a significant retardation of recovery from cSNC relative to downshifted shams. Within-trial analysis of consummatory behavior indicated that ACC lesions facilitated cSNC during both the initial and last 100 s of postshift trials after the first downshift experience, relative to sham controls. These results suggest that the ACC is part of the neural circuit normally involved in coping with the emotional response induced by the incentive downshift event by inducing learning of the new incentive conditions.