Chronic Neuropathic Pain Model Research Articles

Nav1.7 protein and mRNA expression in the dorsal root ganglia of rats with chronic neuropathic pain.

Neuropathic pain was produced by chronic constriction injury of the sciatic nerve in rats. Behavioral tests showed that the thresholds for thermal and mechanical hyperalgesia were significantly reduced in neuropathic pain rats 3–28 days following model induction. The results of immunohistochemistry, western blot assays and reverse transcription-PCR showed that Nav1.7 protein and mRNA expression was significantly increased in the injured dorsal root ganglia. These findings indicated that Nav1.7 might play an important role in the model of chronic neuropathic pain.

MicroRNA-124 as a novel treatment for persistent hyperalgesia

BackgroundChronic pain is often associated with microglia activation in the spinal cord. We recently showed that microglial levels of the kinase G protein–coupled receptor kinase (GRK)2 are reduced in models of chronic pain. We also found that mice with a cell-specific reduction of around 50% in GRK2 level in microglia/macrophages (LysM-GRK2+/− mice) develop prolonged inflammatory hyperalgesia concomitantly with ongoing spinal microglia/macrophage activation. The microRNA miR-124 is thought to keep microglia/macrophages in brain and spinal cord in a quiescent state. In the present study, we investigated the contribution of miR-124 to regulation of hyperalgesia and microglia/macrophage activation in GRK2-deficient mice. In addition, we investigated the effect of miR-124 on chronic inflammatory and neuropathic pain in wild-type (WT) mice.MethodsHyperalgesia was induced by intraplantar IL-1β in WT and LysM-GRK2+/− mice. We determined spinal cord microglia/macrophage miR-124 expression and levels of pro-inflammatory M1 and anti-inflammatory M2 activation markers. The effect of intrathecal miR-124 treatment on IL-1β-induced hyperalgesia and spinal M1/M2 phenotype, and on carrageenan-induced and spared nerve injury-induced chronic hyperalgesia in WT mice was analyzed.ResultsTransition from acute to persistent hyperalgesia in LysM-GRK2+/− mice is associated with reduced spinal cord microglia miR-124 levels. In our LysM-GRK2+/− mice, there was a switch towards a pro-inflammatory M1 phenotype together with increased pro-inflammatory cytokine production. Intrathecal administration of miR-124 completely prevented the transition to persistent pain in response to IL-1β in LysM-GRK2+/− mice. The miR-124 treatment also normalized expression of spinal M1/M2 markers of LysM-GRK2+/− mice. Moreover, intrathecal miR-124 treatment reversed the persistent hyperalgesia induced by carrageenan in WT mice and prevented development of mechanical allodynia in the spared nerve injury model of chronic neuropathic pain in WT mice.ConclusionsWe present the first evidence that intrathecal miR-124 treatment can be used to prevent and treat persistent inflammatory and neuropathic pain. In addition, we show for the first time that persistent hyperalgesia in GRK2-deficient mice is associated with an increased ratio of M1/M2 type markers in spinal cord microglia/macrophages, which is restored by miR-124 treatment. We propose that intrathecal miR-124 treatment might be a powerful novel treatment for pathological chronic pain with persistent microglia activation.

Absence of C–C motif chemokine ligand 5 in mice leads to decreased local macrophage recruitment and behavioral hypersensitivity in a murine neuropathic pain model

Accumulated evidence suggests that the C–C motif chemokine ligand 5 (CCL5) modulates migration of inflammatory cells in several pathological conditions. This study tested the hypothesis that lack of CCL5 would modulate the recruitment of inflammatory cells to painful, inflamed sites and could attenuate pain in a murine chronic neuropathic pain model. Nociceptive sensitization, immune cell infiltration, multiple cytokine expression, and opioid peptide expression in damaged nerves were studied in wild-type (CCL5 +/+) and CCL5-deficient (CCL5 −/−) mice after partial sciatic nerve ligation (PSNL). Results indicated that CCL5 −/− mice had less behavioral hypersensitivity after PSNL. Macrophage infiltration and proinflammatory cytokines (tumor necrosis factor-α, interleukin [IL]-1β, IL-6, and interferon-γ) in damaged nerves following PSNL were significantly decreased in CCL5 −/− mice. Conversely, several antiinflammatory cytokine (IL-4 and IL-10) proteins were significantly increased in CCL5 −/− animals and the expression of enkephalin, β-endorphin, and dynorphin mRNA was significantly lower than in wild-type control mice. These results represent the first evidence that CCL5 is capable of regulating the pathway that controls hyperalgesia at the level of the peripheral injured site in a murine chronic neuropathic pain model. We demonstrated that lack of CCL5 modulated cell infiltration and the proinflammatory milieu within the injured nerve. Attenuated behavioral hypersensitivity in CCL5 −/− mice observed in the current study could be a result of decreased macrophage infiltration, mobilization, and functional ability at injured sites. Collectively, the present study results suggest that CCL5 receptor antagonists may ultimately provide a novel class of analgesics for therapeutic intervention in chronic neuropathic pain.

Pathology of Synapses and Dendritic Spines

Excitatory synapses represent the sites in which axons make a functional contact with their target neurons and they are typically located at the head of dendritic spines. Due to their critical role as mediators of interneuronal interactions, insults to synapses may result with significant clinical manifestations such as dementia or movement disorders. This special issue of Neural Plasticity discusses various aspects of synapse and spine pathology associated with Alzheimer's disease, perinatal asphyxia, and neuropathic pain. Synapse and spine loss may represent early and profound neuropathological changes potentially underlying cognitive deficits in Alzheimer's disease (AD). In fact, synapse loss is the strongest pathological correlate of dementia in AD. The inherent plasticity of synapses makes them an attractive therapeutic target. W. Yu and B. Lu, “Synapses and dendritic spines as pathogenic targets in Alzheimer's disease,” review the important field of synapse and dendritic loss in AD. In their paper, the authors discuss the well-established role of oligomeric amyloid beta in causing synaptic dysfunction and loss through signaling mechanisms associated with long-term depression. They also explore the exciting new relationship between amyloid beta and tau at the postsynaptic density. Several recent studies have placed tau in dendritic spines—a surprising place for a protein that dogma places firmly on microtubules in axons—where it is turning out to mediate amyloid-beta-induced synaptic dysfunction and loss. In another review T. Spires-Jones and S. Knafo, “Spines, plasticity, and cognition in Alzheimer's model mice,” provide a comprehensive analysis on recent works describing the morphological, synaptic, and behavioral characteristics of the different transgenic models of AD. Results from various models and in variety of ages show a gradual deterioration in synaptic and cognitive functions. The accumulating evidence from transgenic models discussed in this review appears to support a model of AD pathogenesis in which oligomeric amyloid beta initiates synaptic dysfunction or degeneration and induces pathological changes in tau, leading to neuronal loss and ultimately to cognitive deficits. G. E. Saraceno et al., “Hippocampal dendritic spines modifications induced by perinatal asphyxia,” investigated the effect of perinatal asphyxia (PA) on the hippocampal postsynaptic density (PSD). They report an unexpected increased thickness and dispersed appearance of the PSD in the asphyctic brains. Correlative fluorescent and electron microscopy showed a decline of F-actin-stained spines in hippocampal excitatory synapses after the insult that may suggest that PA is harmful to the actin cytoskeleton. These data suggest that perinatal asphyxia may lead to long-term changes in hippocampal synapses. NMDA receptors are located at synapses and modulate various forms of synaptic plasticity. Grin1b gene encodes the postsynaptic NMDA receptor in zebrafish. RNA and various RNA products play critical roles in regulating gene expression and production of neuroactive proteins in the nervous system. P. Pozo and B. Hoopengardner, “Identification and characterization of two novel RNA editing sites in grin1b transcripts of embryonic Danio rerio,” identified two novel RNA editing events for the grin1b gene in zebrafish. This new information may have implications for transcriptional regulation of mammalian glutamate receptors, which play essential roles in neuronal transmission and plasticity, but also mediate neuronal toxicity in neurodegenerative disorders. S. K. Kim et al., “Synaptic structure and function in the mouse somatosensory cortex during chronic pain: in vivo two-photon imaging,” summarize recent developments in studying in vivo spine dynamics in thesomatosensory cortex of adult mice in a model of chronic neuropathic pain. Thearticle highlights theimportance of neural plasticity in pain research. Employingmultiphoton microscopy, they describe remarkably rapid synaptic remodeling inlayer 5 neurons of somatosensory cortexwithin days of the peripheral nerveinjury (partial sciatic nerve ligation). Peripheral nerve injury via peripheralhyperactivity causes a rapid rewiring of distinct somatosensory cortexsynapticconnections, leading to local somatosensory cortex hyperexcitability. Theauthors postulate that these local cortical changes in spine turnover followinginduction of neuropathicpain play an important role in chronic pain conditions. Shira Knafo Gunnar K. Gouras Xiao-Xin Yan Tara Spires-Jones

Genetic Enhancement of Neuropathic and Inflammatory Pain by Forebrain Upregulation of CREB-Mediated Transcription

CREB has been reported to be activated by injury and is commonly used as marker for pain-related plasticity changes in somatosensory pathways, including spinal dorsal horn neurons and the anterior cingulate cortex (ACC). However no evidence has been reported to support the direct role of activated CREB in injury-related behavioral sensitization (or allodynia). Here we report that genetic enhancement of CREB-mediated transcription selectively in forebrain areas enhanced behavioral responses to non-noxious stimuli after chronic inflammation (CFA model) or nerve injury. In contrast, behavioral acute responses to peripheral subcutaneous injection of formalin did not show any significant difference. Furthermore, acute pain responses to noxious thermal stimuli were also not affected. Our results thus provide direct evidence that cortical CREB-mediated transcription contributes to behavioral allodynia in animal models of chronic inflammatory or neuropathic pain.

Dysregulated Src upregulation of NMDA receptor activity: a common link in chronic pain and schizophrenia

Upregulation of N-methyl-D-aspartate (NMDA) receptor function by the nonreceptor protein tyrosine kinase Src has been implicated in physiological plasticity at glutamatergic synapses. Here, we highlight recent findings suggesting that aberrant Src upregulation of NMDA receptors may also be key in pathophysiological conditions. Within the nociceptive processing network in the dorsal horn of the spinal cord, pathologically increased Src upregulation of NMDA receptors is critical for pain hypersensitivity in models of chronic inflammatory and neuropathic pain. On the other hand, in the hippocampus and prefrontal cortex, the physiological upregulation of NMDA receptors by Src is blocked by neuregulin 1-ErbB4 signaling, a pathway that is genetically implicated in the positive symptoms of schizophrenia. Thus, either over-upregulation or under-upregulation of NMDA receptors by Src may lead to pathological conditions in the central nervous system. Therefore, normalizing Src upregulation of NMDA receptors may be a novel therapeutic approach for central nervous system disorders, without the deleterious consequences of directly blocking NMDA receptors.

Expression of spinal cord microRNAs in a rat model of chronic neuropathic pain

Neuropathic pain is accompanied by significant alterations of gene expression patterns in the somatosensory nervous system. The spinal cord is particularly prone to neuroplastic changes. Since the expression of microRNAs (miRNAs) has been linked to numerous pathophysiological processes, a contribution of miRNAs to the maladaptive plasticity of the spinal cord in neuropathic pain is possible. Aim of the present study therefore was to characterize the specific expression pattern of miRNAs in the rat spinal cord. Furthermore, we evaluated the time-dependent changes in expression patterns of spinal miRNAs in the chronic constriction injury (CCI) model of neuropathic pain in rats. Results from miRNA microarrays revealed a distinct expression pattern of miRNAs in the rat spinal cord. MiRNAs-494, -720, -690 and -668 showed the highest signal intensities. Members of the let-7 family as well as miR-124 belong to the group of the most highly expressed miRNAs. Induction of neuropathic pain by CCI did not lead to relevant differences in spinal miRNA expression levels compared to sham-operated animals at any studied time point. Therefore, modulation of miRNAs does not seem to contribute significantly to the changes in gene expression that cause neural plasticity in the spinal cord in this model of chronic neuropathic pain.

Spinal cord stimulation of dorsal columns in a rat model of neuropathic pain: Evidence for a segmental spinal mechanism of pain relief

Although spinal cord stimulation (SCS) of the dorsal columns is an established method for treating chronic neuropathic pain, patients still suffer from a substantial level of pain. From a clinical perspective it is known that the location of the SCS is of pivotal importance, thereby suggesting a segmental spinal mode of action. However, experimental studies suggest that SCS acts also through the modulation of supraspinal mechanisms, which might suggest that the location is unimportant. Here we investigated the effect of the rostrocaudal location of SCS stimulation and the effectiveness of pain relief in a rat model of chronic neuropathic pain. Adult male rats (n = 45) were submitted to a partial ligation of the sciatic nerve. The majority of animals developed tactile hypersensitivity in the nerve lesioned paw. All allodynic rats were submitted to SCS (n = 33) for 30 minutes (f = 50 Hz; pulse width 0.2 ms). In one group (n = 16) the electrodes were located at the level where the injured sciatic nerve afferents enter the spinal cord (T13), and in a second group (n = 17) the electrodes were positioned at more rostral levels (T11) as verified by X-ray. A repositioning experiment of electrodes from T12 to T13 was performed in 2 animals. Our data demonstrate that SCS of the dorsal columns at the level where the injured fibers enter the spinal cord dorsal horn result in a much better pain-relieving effect than SCS at more rostral levels. From this we conclude that SCS in treatment of neuropathic pain acts through a segmental spinal site of action.

Validation of an air-puff passive-avoidance paradigm for assessment of aversive learning and memory in rat models of chronic pain

Chronic pain is associated with cognitive deficits. Considerable overlap in brain regions involved in pain and aversion suggests that aversive learning and memory may be affected during chronic pain. Passive-avoidance paradigms traditionally use foot-shock to induce context-conditioned avoidance and may be unsuitable for use in animal models of chronic pain, which are commonly associated with hypersensitivity of the hind-paws. The aim of the present study was to develop and validate a novel passive-avoidance paradigm in rats, employing air-puff as the aversive stimulus, and to use this paradigm to assess aversive learning and memory in rat models of chronic inflammatory and neuropathic pain. Air-puff exposure produced a significant passive-avoidance and this response was attenuated following administration of scopolamine. Nerve-ligated rats and rats injected with complete Freund's adjuvant developed allodynia and hyperalgesia. Air-puff produced a significant passive-avoidance response in both chronic pain models. However, there was no difference in the response between either model and its respective control group. Thus, air-puff can be used as an alternative to foot-shock to induce a passive-avoidance response. The data generated using this model suggest that aversive learning and memory remain intact in the rat spinal nerve ligation and complete Freund's adjuvant models of chronic neuropathic and inflammatory pain, respectively.

Elevated prepronociceptin, nociceptin/orphanin FQ and nocistatin concentrations in rat chronic constriction nerve injury and diabetic neuropathic pain models

Nociceptin/orphanin FQ (N/OFQ) and nocistatin are derived from the same precursor peptide, prepronociceptin. N/OFQ and nocistatin have been postulated to participate in pain modulation. In this study, we investigated whether the prepronociceptin, N/OFQ and nocistatin concentrations in the brain and spinal cord would be altered in chronic constriction injury and diabetic rat neuropathic pain models. Total brain and spinal cord lysates as well as serum from rats that had undergone chronic constriction injury and streptozocin-induced diabetic neuropathy were used to determine the concentrations of three peptides using competitive radioimmunoassay. We found that N/OFQ and prepronociceptin concentrations were significantly raised in both rat neuropathic pain models. Nocistatin was raised in the brains of post traumatic neuropathy pain rats. Overall, our data have demonstrated for the first time that prepronociceptin, N/OFQ and nocistatin concentrations are significantly altered at different tissues of two rat neuropathy pain models.

The M1/M4 preferring agonist xanomeline is analgesic in rodent models of chronic inflammatory and neuropathic pain via central site of action

The role of muscarinic receptor subtype-1 (M1) in chronic pain is unclear. In an attempt to gain an understanding of its role, we have tested xanomeline, an M1/M4-preferring agonist, together with nonselective (scopolamine and pirenzepine), and selective (MT-7 and MT-3) muscarinic receptor (M1 and M4, respectively) antagonists in a number of inflammatory and neuropathic pain models. Xanomeline potently and effectively reversed tactile allodynia and heat hyperalgesia associated with established neuropathic and inflammatory pain in both rat and mouse models. Scopolamine and pirenzepine completely blocked the analgesic response to xanomeline, confirming that the analgesic effect is mediated by the muscarinic system. The highly selective M1 receptor toxin, MT-7, almost completely abolished the analgesic response to xanomeline when administered supraspinally. However, the highly selective M4 receptor toxin, MT-3, only marginally reversed the analgesia when given supraspinally, and had no effect when given spinally. In conclusion, the data presented show that the nonselective muscarinic agonist xanomeline is analgesic in models of persistent pain and suggest that the activation of supraspinal M1 receptors, and to a lesser extent supraspinal M4 receptors, contributes to that analgesia.

Plant derived alkaloid (−)-cassine induces anti-inflammatory and anti-hyperalgesics effects in both acute and chronic inflammatory and neuropathic pain models

Natural products have been revealed as relevant sources of therapeutic agents including those for the management of pain states. In this study, the anti-nociceptive and anti-inflammatory effects of (−)-cassine, isolated from Senna spectabilis were evaluated using pharmacological, behavioural and biochemical approaches. Oral treatment with (−)-cassine (3–30 mg/kg) reduced carrageenan-induced mechanical and thermal nociception associated with the suppression of myeloperoxidase activity in the mouse paw. Moreover, (−)-cassine (1–10 μg/site) prevented mechanical hyperalgesia induced by carrageenan when given through the intraplantar (i.pl.), spinal and intracerebroventricular routes. Additionally, oral treatment with (−)-cassine (3–60 mg/kg) prevented the mechanical hyperalgesia elicited by intraplantar injection of prostaglandin E 2, complete Freund’s adjuvant, interleukin-1β, interleukin-6 and keratinocyte-derived chemokine. Furthermore, (−)-cassine inhibited the mechanical nociceptive response induced by ligation of the sciatic nerve and also significantly reduced the levels of cytokines/chemokines in paw tissue following i.pl. injection of carrageenan. In addition, the anti-nociceptive and anti-inflammatory actions of (−)-cassine were associated with its ability to interact with both TRPV1 and TRPA1 receptors and by inhibiting the upregulation of cyclooxigenase-2 as well as inhibiting the phosphorylation of MAPK/ERK and the transcription factor NF-κB. It is important to highlight that oral treatment with (−)-cassine did not produce any effects related to temperature, locomotor activity or catalepsy. Altogether, the present data demonstrate that (−)-cassine has systemic, spinal and supraspinal anti-nociceptive properties when assessed in inflammatory and neuropathic pain models. These effects are associated with its ability to block several signalling pathways associated with inflammatory and nociceptive responses. This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

The antihyperalgesic effect of cytidine-5′-diphosphate-choline in neuropathic and inflammatory pain models

This study was designed to test the effects of intracerebroventricularly (i.c.v.) administered CDP-choline (cytidine-5'-diphosphate-choline; citicoline) and its metabolites in rat models of inflammatory and neuropathic pain. The i.c.v. administration of CDP-choline (0.5, 1.0 and 2.0 µmol) produced a dose and time-dependent reversal of mechanical hyperalgesia in both carrageenan-induced inflammatory and chronic constriction injury-induced neuropathic pain models in rats. The antihyperalgesic effect of CDP-choline was similar to that observed with an equimolar dose of choline (1 µmol). The CDP-choline-induced antihyperalgesic effect was prevented by central administration of the neuronal high-affinity choline uptake inhibitor hemicholinium-3 (1 µg), the nonselective nicotinic receptor antagonist mecamylamine (50 µg), the α7-selective nicotinic ACh receptor antagonist, α-bungarotoxin (2 µg) and the γ-aminobutyric acid B receptor antagonist CGP-35348 (20 µg). In contrast, i.c.v. pretreatment with the nonselective opioid receptor antagonist naloxone (10 µg) only prevented the CDP-choline-induced antihyperalgesic effect in the neuropathic pain model while the nonselective muscarinic receptor antagonist atropine (10 µg) did not alter the antihyperalgesic effect in the two models. These results indicate that CDP-choline-elicited antihyperalgesic effect in different models of pain occurs through mechanisms that seem to involve an interaction with supraspinal α7-selective nicotinic ACh receptors, and γ-aminobutyric acid B receptors, whereas central opioid receptors have a role only in the neuropathic pain model.

Involvement of the mu-opioid receptor in opioid tolerance induced by the intermittent administration of fentanyl in a rat chronic neuropathic pain model

Involvement of the mu-opioid receptor in opioid tolerance induced by the intermittent administration of fentanyl in a rat chronic neuropathic pain model

Intravenous neural stem cells abolish hypersensitivity in the mouse chronic constriction injury neuropathic pain model: Focus on cytokines and nerve repair

Intravenous neural stem cells abolish hypersensitivity in the mouse chronic constriction injury neuropathic pain model: Focus on cytokines and nerve repair

Tapentadol in the management of chronic low back pain: a novel approach to a complex condition?

Chronic pain affects approximately 1 in 5 people in Europe, and around half of sufferers receive inadequate pain management. The most common location is the lower back. Pharmacological treatment of this condition is challenging because of the range of causative mechanisms and the difficulty of balancing analgesic efficacy and tolerability. An international panel of clinical pain specialists met in September, 2009, to discuss the treatment of chronic low back pain, and to review preclinical and clinical data relating to the new analgesic, tapentadol. A lack of consensus exists on the best treatment for low back pain. The range of regularly prescribed pharmacological agents extends from nonopioids (paracetamol, NSAIDs, and COX-2 inhibitors) to opioids, antidepressants and anticonvulsants. Pain relief may be compromised, however, by an undetected neuropathic component or intolerable side effects. Treatment is potentially life-long and effective analgesics are urgently needed, with demonstrable long-term safety. Combining separate agents with different mechanisms of action could overcome the limitations of present pharmacological therapy, but clinical evidence for this approach is currently lacking. Tapentadol combines μ-opioid agonism with noradrenaline reuptake inhibition in a single molecule. There is strong evidence of synergistic antinociception between these two mechanisms of action. In preclinical and clinical testing, tapentadol has shown efficacy against both nociceptive and neuropathic pain. Preclinical data indicate that tapentadol’s μ-opioid agonism makes a greater contribution to analgesia in acute pain, while noradrenaline reuptake inhibition makes a greater contribution in chronic neuropathic pain models. Tapentadol also produces fewer adverse events than oxycodone at equianalgesic doses, and thus may have a ‘μ-sparing effect’. Current evidence indicates that tapentadol’s efficacy/tolerability ratio may be better than those of classical opioids. However, further research is needed to establish its role in pain management.

Nonselective and NR2B-selective N -methyl-d-aspartic Acid Receptor Antagonists Produce Antinociception and Long-term Relief of Allodynia in Acute and Neuropathic Pain

At low dose, the nonselective N-methyl-D-aspartate receptor antagonist ketamine produces potent analgesia. In humans, psychedelic side effects limit its use. To assess whether other N-methyl-D-aspartate receptor antagonist have an improved therapeutic utility index, we compared antinociceptive, side effect, and locomotor activity of three N-methyl-D-aspartate receptor antagonists. Ketamine, its active metabolite norketamine, and the NR2B-selective antagonist traxoprodil (CP-101,606) were tested in rat models of acute antinociception (paw-withdrawal response to heat) and chronic neuropathic pain (spared nerve injury). Side effects (stereotypical behavior, activity level) were scored and locomotor function of the nerve-injured paw was assessed using computerized gait analysis. In the chronic pain model, treatment was given 7 days after surgery, for 3 h on 5 consecutive days. All three N-methyl-D-aspartate receptor antagonists caused dose-dependent antinociception in the acute pain model and relief of mechanical and cold allodynia for 3-6 weeks after treatment in the chronic pain model (P < 0.05 vs. saline). In both tests, ketamine was most potent. Norketamine was as much as two times less potent and traxoprodil was up to 8 times less potent than ketamine (based on area under the curve measures). Nerve injury caused an inability to use the affected paw that either did not improve after treatment (ketamine, traxoprodil) or showed only a limited effect (norketamine). Traxoprodil, but not ketamine or norketamine, showed clear separation between effect and side effect. The observation that traxoprodil causes relief of chronic pain outlasting the treatment period with no side effects makes it an attractive alternative to ketamine in the treatment of chronic neuropathic pain.

Is finding the common biological link(s) between pain and affect an infinity quest?

Clinical studies have demonstrated comorbidity between painand depression or anxiety [1,2]. The prevalence of depression inpatientswithchronicpainreaches5–100%,theprevalenceofanxi-etydisorderreaches11–60%,andtheprevalenceofpaininpatientswithdepressiondisorderreaches15–100%dependingonthestudyand type of pain [3,4]. These comorbidities affect negatively thelife of the patients. It is still not clear whether there is a causalrelationship in the development of comorbidity between chronicpain and anxiety/depression or whether chronic pain and anxi-ety/depression have distinctly different mechanisms that coexistindependentofeachother.Thisquestionisnotonlyofconsiderableacademic interest but also of potential clinical importance whendevelopingtherapeuticinterventionsforthecomorbidchronicpainand affective disorder.Experimental animal studies have shown that chronic neuro-pathic pain is associated with structural and functional changes inbrain areas that are important for processing of emotions, such astheamygdala[5–8].Sincebrainareasimportantforemotionshavereciprocalconnectionswithpain-relaynucleiandplayaroleinreg-ulation of pain [9], it might be speculated that the functional andstructuralchangesintheseareasprovideacommonmechanismformaintenanceofpainandaffectchanges,suchasdepressionoranx-iety. In line with this proposal, some [5,10–12], but not all [13,14],studies with experimental animal models of chronic neuropathicpain have demonstrated co-occurrence of anxiety or depression,which, however, has varied depending on many factors. Amongthem are the age of the animals, the duration of the pathophysi-ological condition, and the type of affect studied [12]. Moreover,since genetic factors are known to influence both the developmentofchronicpain[15]andaffectivestates[16],itislikelythatgeneticfactors also play an important role in their comorbidity.Among potential common molecular and neurochemical linksbetween pain and anxiety is corticotropin-releasing factor (CRF)anditsCRF

Inflammation Confers Dual Effects on Nociceptive Processing in Chronic Neuropathic Pain Model

Although inflammation induces pain, immune cells also produce mediators that can effectively counteract it. To further elucidate the role of the immune response, we analyzed the relationship of pain behavior, several inflammatory signals, and opioid peptides using partial sciatic nerve ligation in mice at different levels of immunocompromise. Sciatic nerves of C57BL/6C, nonobese diabetic (NOD), or nonobese diabetic-severe combined immune deficiency (NOD-SCID) mice were partially ligated. Responses to mechanical and radiant heat stimuli were observed. Inflammation was detected by immunohistochemistry and flow cytometry. Inflammatory cytokines and opioid peptides were analyzed using real-time polymerase chain reaction and enzyme-linked immunosorbent assay or immunostaining. Inflammation in immunocompromised mice was subordinate when compared with that seen in C57BL/6C mice. In addition, immunocompromised mice had less pain hypersensitivity at early stages. Whereas proinflammatory tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), and interferon-γ (IFN-γ), as well as antiinflammatory interleukin 1 receptor antagonist (IL-1Ra), interleukin 4 (IL-4), interleukin 10 (IL-10), and interleukin 13 (IL-13) cytokine expression and protein were increased in C57BL/6C mice, they were lower in immunocompromised mice. Although enkephalin, dynorphin, and β-endorphin messenger RNA expression also increased in C57BL/6C mice, peaking on day 14, this result was not observed in immunocompromised mice. The contribution of inflammation to nerve injury is complex with biphasic modulation. During the early phase, a wide range of proinflammatory cytokines are released, leading to enhanced pain. In contrast, the analgesic effect of opioid peptides and antiinflammatory cytokines was more predominate in the later phases of injury, leading to attenuated pain responses.

The antinociceptive and antihyperalgesic effect of tapentadol is partially retained in OPRM1 (μ-opioid receptor) knockout mice

Activation of the μ-opioid receptor (MOR) and noradrenaline reuptake inhibition (NRI) are well recognized as analgesic principles in acute and chronic pain indications. The novel analgesic tapentadol combines MOR agonism and NRI in a single molecule. The present study used OPRM1 (MOR) knockout (KO) mice to determine the relative contribution of MOR activation to tapentadol-induced analgesia in models of acute (nociceptive) and chronic (neuropathic) pain. Antinociceptive efficacy was inferred from paw withdrawal latencies on a 48 °C hot plate in naive animals. Antihyperalgesic efficacy was inferred from the number of nocifensive reactions in diabetic animals (streptozotocin-induced) and non-diabetic controls on a 50 °C hot plate. The effect of tapentadol (0.316–31.6 mg/kg IP) and the MOR agonist morphine (3–10 mg/kg IP) was determined in OPRM1 KO- and congenic wildtype mice. At baseline, diabetic OPRM1 KO mice showed reduced nocifensive reactions as compared to diabetic wildtype mice. In both pain models, morphine and tapentadol were effective in wildtype mice. In the KO mice, however, morphine failed to produce analgesia in either model. On the other hand, tapentadol still had clear effects, and when tested at a dose that was fully efficacious in wildtype mice, showed reduced but still significant antinociceptive efficacy in non-diabetic, and antihyperalgesic efficacy in diabetic OPRM1 KO mice. The remaining antinociceptive activity of tapentadol in OPRM1 KO mice was abolished by the α 2-adrenoceptor antagonist yohimbine. In OPRM1 wildtype mice, the antihyperalgesic effect of tapentadol was 10 times more potent in diabetic animals (ED 50 = 1.10 mg/kg) than its antinociceptive effect in naïve animals (ED 50 = 10.8 mg/kg). This study supports the conclusion that the analgesic effect of tapentadol is only partly due to the activation of MOR, both under acute and chronic pain conditions, and that the efficacy of tapentadol against acute and chronic pain is based on its combined mechanism of action.