A back-translational study of descending interactions with the induction of hyperalgesia by high-frequency electrical stimulation in rat and human.

ABSTRACT: In humans and animals, high-frequency electrocutaneous stimulation (HFS) induces an "early long-term potentiation-like" sensitisation, where synaptic plasticity is underpinned by an ill-defined interaction between peripheral input and central modulatory processes. The relative contributions of these processes to the initial pain or nociceptive response likely differ from those that underpin development of the heightened response. To investigate the impact of HFS-induced hyperalgesia on pain and nociception in perception and neural terms, respectively, and to explore the impact of descending inhibitory pathway activation on the development of HFS-induced hyperalgesia, we performed parallel studies utilising identical stimuli to apply HFS concurrent to (1) a conditioned pain modulation paradigm during psychophysical testing in healthy humans or (2) a diffuse noxious inhibitory controls paradigm during in vivo electrophysiological recording of spinal neurones in healthy anaesthetised rats. High-frequency electrocutaneous stimulation alone induced enhanced perceptual responses to pinprick stimuli in cutaneous areas secondary to the area of electrical stimulation in humans and increased the excitability of spinal neurones which exhibited stimulus intensity-dependent coded responses to pinprick stimulation in a manner that tracked with human psychophysics, supporting their translational validity. Application of a distant noxious conditioning stimulus during HFS did not alter perceived primary or secondary hyperalgesia in humans or the development of primary or secondary neuronal hyperexcitability in rats compared with HFS alone, suggesting that, upon HFS-response initiation in a healthy nervous system, excitatory signalling escapes inhibitory control. Therefore, in this model, dampening facilitatory mechanisms rather than augmenting top-down inhibitions could prevent pain development.

Ambroxol for neuropathic pain: hiding in plain sight?

ABSTRACT: Ambroxol is a multifaceted drug with primarily mucoactive and secretolytic actions, along with anti-inflammatory, antioxidant, and local anaesthetic properties. It has a long history of use in the treatment of respiratory tract diseases and has shown to be efficacious in relieving sore throat. In more recent years, ambroxol has gained interest for its potential usefulness in treating neuropathic pain. Research into this area has been slow, despite clear preclinical evidence to support its primary analgesic mechanism of action-blockade of voltage-gated sodium (Na v ) channels in sensory neurons. Ambroxol is a commercially available inhibitor of Na v 1.8, a crucial player in the pathophysiology of neuropathic pain, and Na v 1.7, a particularly exciting target for the treatment of chronic pain. In this review, we discuss the analgesic mechanisms of action of ambroxol, as well as proposed synergistic properties, followed by the preclinical and clinical results of its use in the treatment of persistent pain and neuropathic pain symptoms, including trigeminal neuralgia, fibromyalgia, and complex regional pain syndrome. With its well-established safety profile, extensive preclinical and clinical drug data, and early evidence of clinical effectiveness, ambroxol is an old drug worthy of further investigation for repurposing. As a patent-expired drug, a push is needed to progress the drug to clinical trials for neuropathic pain. We encourage the pharmaceutical industry to look at patented drug formulations and take an active role in bringing an optimized version for neuropathic pain to market.

Nerve injury increases native Ca V 2.2 trafficking in dorsal root ganglion mechanoreceptors.

ABSTRACT: Neuronal N-type (Ca V 2.2) voltage-gated calcium channels are essential for neurotransmission from primary afferent terminals in the dorsal horn. In this study, we have used a knockin mouse containing Ca V 2.2 with an inserted extracellular hemagglutinin tag (Ca V 2.2_HA), to visualise the pattern of expression of endogenous Ca V 2.2 in dorsal root ganglion (DRG) neurons and their primary afferents in the dorsal horn. We examined the effect of partial sciatic nerve ligation (PSNL) and found an increase in Ca V 2.2_HA only in large and medium dorsal root ganglion neurons and also in deep dorsal horn synaptic terminals. Furthermore, there is a parallel increase in coexpression with GFRα1, present in a population of low threshold mechanoreceptors, both in large DRG neurons and in their terminals. The increased expression of Ca V 2.2_HA in these DRG neurons and their terminals is dependent on the presence of the auxiliary subunit α 2 δ-1, which is required for channel trafficking to the cell surface and to synaptic terminals, and it likely contributes to enhanced synaptic transmission at these synapses following PSNL. By contrast, the increase in GFRα1 is not altered in α 2 δ-1-knockout mice. We also found that following PSNL, there is patchy loss of glomerular synapses immunoreactive for Ca V 2.2_HA and CGRP or IB4, restricted to the superficial layers of the dorsal horn. This reduction is not dependent on α 2 δ-1 and likely reflects partial deafferentation of C-nociceptor presynaptic terminals. Therefore, in this pain model, we can distinguish 2 different events affecting specific DRG terminals, with opposite consequences for Ca V 2.2_HA expression and function in the dorsal horn.

Maximizing treatment efficacy through patient stratification in neuropathic pain trials.

Treatment of neuropathic pain remains inadequate despite the elucidation of multiple pathophysiological mechanisms and the development of promising therapeutic compounds. The lack of success in translating knowledge into clinical practice has discouraged pharmaceutical companies from investing in pain medicine; however, new patient stratification approaches could help bridge the translation gap and develop individualized therapeutic approaches. As we highlight in this article, subgrouping of patients according to sensory profiles and other baseline characteristics could aid the prediction of treatment success. Furthermore, novel outcome measures have been developed for patients with neuropathic pain. The extent to which sensory profiles and outcome measures can be employed in routine clinical practice and clinical trials and across distinct neuropathic pain aetiologies is yet to be determined. Improvements in animal models, drawing on our knowledge of human pain, and robust public-private partnerships will be needed to pave the way to innovative and effective pain medicine in the future.

Sodium-calcium exchanger-3 regulates pain "wind-up": From human psychophysics to spinal mechanisms.

Repeated application of noxious stimuli leads to a progressively increased pain perception; this temporal summation is enhanced in and predictive of clinical pain disorders. Its electrophysiological correlate is "wind-up," in which dorsal horn spinal neurons increase their response to repeated nociceptor stimulation. To understand the genetic basis of temporal summation, we undertook a GWAS of wind-up in healthy human volunteers and found significant association with SLC8A3 encoding sodium-calcium exchanger type 3 (NCX3). NCX3 was expressed in mouse dorsal horn neurons, and mice lacking NCX3 showed normal, acute pain but hypersensitivity to the second phase of the formalin test and chronic constriction injury. Dorsal horn neurons lacking NCX3 showed increased intracellular calcium following repetitive stimulation, slowed calcium clearance, and increased wind-up. Moreover, virally mediated enhanced spinal expression of NCX3 reduced central sensitization. Our study highlights Ca2+ efflux as a pathway underlying temporal summation and persistent pain, which may be amenable to therapeutic targeting.

Neuropharmacological basis for multimodal analgesia in chronic pain.

Managing chronic pain remains a major unmet clinical challenge. Patients can be treated with a range of interventions, but pharmacotherapy is the most common. These include opioids, antidepressants, calcium channel modulators, sodium channel blockers, and nonsteroidal anti-inflammatory drugs. Many of these drugs target a particular mechanism; however, chronic pain in many diseases is multifactorial and induces plasticity throughout the sensory neuroaxis. Furthermore, comorbidities such as depression, anxiety, and sleep disturbances worsen quality of life. Given the complexity of mechanisms and symptoms in patients, it is unsurprising that many fail to achieve adequate pain relief from a single agent. The efforts to develop novel drug classes with better efficacy have not always proved successful; a multimodal or combination approach to analgesia is an important strategy in pain control. Many patients frequently take more than one medication, but high-quality evidence to support various combinations is often sparse. Ideally, combining drugs would produce synergistic action to maximize analgesia and reduce side effects, although sub-additive and additive analgesia is still advantageous if additive side-effects can be avoided. In this review, we discuss pain mechanisms, drug actions, and the rationale for mechanism-led treatment selection.Abbreviations: COX - cyclooxygenase, CGRP - calcitonin gene-related peptide, CPM - conditioned pain modulation, NGF - nerve growth factor, NNT - number needed to treat, NMDA - N-methyl-d-aspartate, NSAID - nonsteroidal anti-inflammatory drugs, TCA - tricyclic antidepressant, SNRI - serotonin-noradrenaline reuptake inhibitor, QST - quantitative sensory testing.

Studying Independent Kcna6 Knock-out Mice Reveals Toxicity of Exogenous LacZ to Central Nociceptor Terminals and Differential Effects of Kv1.6 on Acute and Neuropathic Pain Sensation.

The potassium channel Kv1.6 has recently been implicated as a major modulatory channel subunit expressed in primary nociceptors. Furthermore, its expression at juxtaparanodes of myelinated primary afferents is induced following traumatic nerve injury as part of an endogenous mechanism to reduce hyperexcitability and pain-related hypersensitivity. In this study, we compared two mouse models of constitutive Kv1.6 knock-out (KO) achieved by different methods: traditional gene trap via homologous recombination and CRISPR-mediated excision. Both Kv1.6 KO mouse lines exhibited an unexpected reduction in sensitivity to noxious heat stimuli, to differing extents: the Kv1.6 mice produced via gene trap had a far more significant hyposensitivity. These mice (Kcna6lacZ ) expressed the bacterial reporter enzyme LacZ in place of Kv1.6 as a result of the gene trap mechanism, and we found that their central primary afferent presynaptic terminals developed a striking neurodegenerative phenotype involving accumulation of lipid species, development of "meganeurites," and impaired transmission to dorsal horn wide dynamic range neurons. The anatomic defects were absent in CRISPR-mediated Kv1.6 KO mice (Kcna6-/-) but were present in a third mouse model expressing exogenous LacZ in nociceptors under the control of a Nav1.8-promoted Cre recombinase. LacZ reporter enzymes are thus intrinsically neurotoxic to sensory neurons and may induce pathologic defects in transgenic mice, which has confounding implications for the interpretation of gene KOs using lacZ Nonetheless, in Kcna6-/- mice not affected by LacZ, we demonstrated a significant role for Kv1.6 regulating acute noxious thermal sensitivity, and both mechanical and thermal pain-related hypersensitivity after nerve injury.SIGNIFICANCE STATEMENT In recent decades, the expansion of technologies to experimentally manipulate the rodent genome has contributed significantly to the field of neuroscience. While introduction of enzymatic or fluorescent reporter proteins to label neuronal populations is now commonplace, often potential toxicity effects are not fully considered. We show a role of Kv1.6 in acute and neuropathic pain states through analysis of two mouse models lacking Kv1.6 potassium channels: one with additional expression of LacZ and one without. We show that LacZ reporter enzymes induce unintended defects in sensory neurons, with an impact on behavioral data outcomes. To summarize we highlight the importance of Kv1.6 in recovery of normal sensory function following nerve injury, and careful interpretation of data from LacZ reporter models.

The impact of bone cancer on the peripheral encoding of mechanical pressure stimuli.

Skeletal metastases are frequently accompanied by chronic pain that is mechanoceptive in nature. Mechanistically, cancer-induced bone pain (CIBP) is mediated by peripheral sensory neurons innervating the cancerous site, the cell bodies of which are housed in the dorsal root ganglia (DRG). How these somatosensory neurons encode sensory information in CIBP remains only partly explained. Using a validated rat model, we first confirmed cortical bone destruction in CIBP but not sham-operated rats (day 14 after surgery, designated "late"-stage bone cancer). This occurred with behavioural mechanical hypersensitivity (Kruskal-Wallis H for independent samples; CIBP vs sham-operated, day 14; P < 0.0001). Next, hypothesising that the proportion and phenotype of primary afferents would be altered in the disease state, dorsal root ganglia in vivo imaging of genetically encoded calcium indicators and Markov Cluster Analysis were used to analyse 1748 late-stage CIBP (n = 10) and 757 sham-operated (n = 9), neurons. Distinct clusters of responses to peripheral stimuli were revealed. In CIBP rats, upon knee compression of the leg ipsilateral to the tumour, (1) 3 times as many sensory afferents responded (repeated-measures analysis of variance: P < 0.0001 [vs sham]); (2) there were significantly more small neurons responding (Kruskal-Wallis for independent samples (vs sham): P < 0.0001); and (3) approximately 13% of traced tibial cavity afferents responded (no difference observed between CIBP and sham-operated animals). We conclude that an increased sensory afferent response is present in CIBP rats, and this is likely to reflect afferent recruitment from outside of the bone rather than increased intraosseous afferent activity.

Capsaicin 8% dermal patch in clinical practice: an expert opinion.

INTRODUCTION: Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system, which can severely impact patients' quality of life. The current-approved treatments for NP comprise of both centrally acting agents and topical drugs, including capsaicin 8% dermal patches, which is approved for the treatment of peripheral NP. AREAS COVERED: The authors summarize literature data regarding capsaicin use in patients who suffer from NP and discuss the clinical applications of this topical approach. EXPERT OPINION: Overall, the capsaicin 8% dermal patch is as effective in reducing pain intensity as other centrally active agents (i.e. pregabalin). Some studies have also reported fewer systemic side effects, a faster onset of action and superior treatment satisfaction compared with systemic agents. In our opinion, capsaicin 8% dermal patches also present additional advantages, such as a good systemic tolerability, the scarcity of adverse events, the possibility to combine it with other agents, and a good cost-effective profile. It is important to note that, as the mechanism of action of capsaicin 8% is the 'defunctionalization' of small afferent fibers through interaction with TRPV1 receptors, the peripheral expression of this receptor on nociceptor fibers, is crucial to predict patient's response to treatment.

Translational issues in precision medicine in neuropathic pain.

Neuropathic pain remains poorly treated, with most new drugs falling through the translational gap. The traditional model of bench-to-bedside research has relied on identifying new mechanisms/targets in animal models and then developing clinical applications. Several have advocated bridging the translational gap by beginning with clinical observations and back-translating to animal models for further investigation of mechanisms. There is good evidence that phenotyping of patients through quantitative sensory testing can lead to improved treatment selection and hence improved patient outcomes. This practice has been widely adopted in clinical investigations, but its application in preclinical research is not mainstream. In this review, we retrospectively examine our historical rodent data sets with the aim of reconsidering drug effects on sensory neuronal endpoints, their alignment with clinical observations, and how these might guide future clinical studies.

La douleur neuropathique reste mal traitée, alors que la plupart des nouveaux médicaments ne réussissent pas à franchir le fossé translationnel. Le modèle traditionnel de la recherche, du laboratoire au chevet du patient, repose sur l'identification de nouveaux mécanismes ou cibles dans des modèles animaux, suivie du développement d'applications cliniques. Certains préconisent de combler le fossé de la recherche translationnelle en commençant par des observations cliniques et en les transposant ensuite sur des modèles animaux afin d'approfondir l'étude des mécanismes. Il est bien établi que le phénotypage des patients par des tests sensoriels quantitatifs peut conduire à une meilleure sélection des traitements et, par conséquent, à de meilleurs résultats pour les patients. Ces pratiques ont été largement adoptées dans les enquêtes cliniques, mais leur application dans la recherche préclinique n'est pas généralisée. Dans cette revue, nous examinons rétrospectivement nos ensembles de données historiques sur les rongeurs dans le but de reconsidérer les effets des médicaments sur les paramètres neuronaux sensoriels, leur alignement avec les observations cliniques et la manière dont celles-ci pourraient orienter les études cliniques futures.

Modulation of sensitization processes in the management of pain and the importance of descending pathways: a role for tapentadol?

Objective: This paper presents and discusses recent evidence on the pathophysiological mechanisms of pain. The role of tapentadol - an opioid characterized by an innovative mechanism of action (i.e. µ-opioid receptor [MOR] agonism and inhibition of noradrenaline [NA] reuptake [NRI]) - in the modulation of pain, and the most recent pharmacological evidence on this molecule (e.g. the µ-load concept) are also presented and commented upon.Methods: Narrative review.Results: Solid evidence has highlighted the importance of central sensitization in the transition from acute to chronic pain. In particular, the noradrenergic system holds a major role in limiting central sensitization and the progression to chronic pain. Therefore, pharmacological modulation of the noradrenergic system appears to be a well-grounded strategy for the control of chronic pain. Tapentadol is characterized by a to-date-unique mechanism of action, since it acts both as a MOR agonist and as an inhibitor of NA reuptake. The synergistic interaction of these two mechanisms allows a strong analgesic effect by acting on both ascending and descending pathways. Of note, the reduced µ-load of tapentadol limits the risk of opioid-related adverse events, such as gastrointestinal disturbances. Moreover, the NA component becomes predominant, at least, in some types of pain, with consequent specific clinical efficacy in the treatment of neuropathic and chronic pain.Conclusions: According to these characteristics, tapentadol appears suitable in the treatment of severe uncontrolled chronic pain characterized by both a nociceptive and a neuropathic component, such as osteoarthritis or back pain.

Supraspinal Opioid Circuits Differentially Modulate Spinal Neuronal Responses in Neuropathic Rats.

BACKGROUND: The anterior cingulate cortex and central nucleus of the amygdala connect widely with brainstem nuclei involved in descending modulation, including the rostral ventromedial medulla. Endogenous opioids in these circuits participate in pain modulation. The hypothesis was that a differential opioidergic role for the brain nuclei listed in regulation of spinal neuronal responses because separable effects on pain behaviors in awake animals were previously observed. METHODS: This study utilized in vivo electrophysiology to determine the effects of morphine microinjection into the anterior cingulate cortex, right or left central nucleus of the amygdala, or the rostral ventromedial medulla on spinal wide dynamic range neuronal responses in isoflurane-anesthetized, male Sprague-Dawley rats. Ongoing activity in the ventrobasal thalamus was also measured. In total, 33 spinal nerve ligated and 26 control age- and weight-matched control rats were used. RESULTS: Brainstem morphine reduced neuronal firing to 60-g von Frey stimulation in control rats (to 65 ± 12% of control response (means ± 95% CI), P < 0.001) with a greater inhibition in neuropathic rats (to 53 ± 17% of control response, P < 0.001). Contrasting anterior cingulate cortex morphine had only marginal modulatory effects on spinal neuronal responses with limited variance in effect between control and neuropathic rats. The inhibitory effects of morphine in the central nucleus of the amygdala were dependent on pain state and laterality; only right-side morphine reduced neuronal firing to 60-g stimulation in neuropathic rats (to 65 ± 14% of control response, P = 0.001). In addition, in neuropathic rats elevated ongoing neuronal activity in the ventral posterolateral thalamus was not inhibited by anterior cingulate cortex morphine, in contrast to evoked responses. CONCLUSIONS: Cumulatively the data support opioid modulation of evoked responses predominately through a lateralized output from the right amygdala, as well as from the brainstem that is enhanced in injured conditions. Minimal modulation of dorsal horn responses was observed after anterior cingulate cortex opioid administration regardless of injury state.

Neuropathic Pain: Mechanism-Based Therapeutics.

Neuropathic pain (NeP) can result from sources as varied as nerve compression, channelopathies, autoimmune disease, and incision. By identifying the neurobiological changes that underlie the pain state, it will be clinically possible to exploit mechanism-based therapeutics for maximum analgesic effect as diagnostic accuracy is optimized. Obtaining sufficient knowledge regarding the neuroadaptive alterations that occur in a particular NeP state will result in improved patient analgesia and a mechanism-based, as opposed to a disease-based, therapeutic approach to facilitate target identification. This will rely on comprehensive disease pathology insight; our knowledge is vastly improving due to continued forward and back translational preclinical and clinical research efforts. Here we discuss the clinical aspects of neuropathy and currently used drugs whose mechanisms of action are outlined alongside their clinical use. Finally, we consider sensory phenotypes, patient clusters, and predicting the efficacy of an analgesic for neuropathy.

GPR160 de-orphanization reveals critical roles in neuropathic pain in rodents.

Treating neuropathic pain is challenging and novel non-opioid-based medicines are needed. Using unbiased receptomics, transcriptomic analyses, immunofluorescence, and in situ hybridization, we found that the expression of the orphan GPCR Gpr160 and GPR160 increased in the rodent dorsal horn of the spinal cord following traumatic nerve injury. Genetic and immunopharmacological approaches demonstrated that GPR160 inhibition in the spinal cord prevented and reversed neuropathic pain in male and female rodents without altering normal pain response. GPR160 inhibition in the spinal cord attenuated sensory processing in the thalamus, a key relay in the sensory discriminative pathways of pain. We also identified cocaine- and amphetamine-regulated transcript peptide (CARTp) as a GPR160 ligand. Inhibiting endogenous CARTp signaling in spinal cord attenuated neuropathic pain, whereas exogenous intrathecal CARTp evoked painful hypersensitivity through GPR160-dependent ERK and cAMP response element-binding protein (CREB). Our findings de-orphanize GPR160, identify it as a determinant of neuropathic pain and potential therapeutic target, and provide insights into its signaling pathways. CARTp is involved in many diseases including depression and reward and addiction; de-orphanization of GPR160 is a major step forward understanding the role of CARTp signaling in health and disease.

Unusual Pain Disorders - What Can Be Learned from Them?

Pain is common in many different disorders and leads to a significant reduction in quality of life in the affected patients. Current treatment options are limited and often result in insufficient pain relief, partly due to the incomplete understanding of the underlying pathophysiological mechanisms. The identification of these pathomechanisms is therefore a central object of current research. There are also a number of rare pain diseases, that are generally little known and often undiagnosed, but whose correct diagnosis and examination can help to improve the management of pain disorders in general. In some of these unusual pain disorders like sodium-channelopathies or sensory modulation disorder the underlying pathophysiological mechanisms have only recently been unravelled. These mechanisms might serve as pharmacological targets that may also play a role in subgroups of other, more common pain diseases. In other unusual pain disorders, the identification of pathomechanisms has already led to the development of new drugs. A completely new therapeutic approach, the gene silencing, can even stop progression in hereditary transthyretin amyloidosis and porphyria, ie in pain diseases that would otherwise be rapidly fatal if left untreated. Thus, pain therapists and researchers should be aware of these rare and unusual pain disorders as they offer the unique opportunity to study mechanisms, identify new druggable targets and finally because early diagnosis might save many patient lives.

A study of cortical and brainstem mechanisms of diffuse noxious inhibitory controls in anaesthetised normal and neuropathic rats.

Diffuse noxious inhibitory controls (DNIC) are a mechanism of endogenous descending pain modulation and are deficient in a large proportion of chronic pain patients. However, the pathways involved remain only partially determined with several cortical and brainstem structures implicated. This study examined the role of the dorsal reticular nucleus (DRt) and infralimbic (ILC) region of the medial prefrontal cortex in DNIC. In vivo electrophysiology was performed to record from dorsal horn lamina V/VI wide dynamic range neurones with left hind paw receptive fields in anaesthetised sham-operated and L5/L6 spinal nerve-ligated (SNL) rats. Evoked neuronal responses were quantified in the presence and absence of a conditioning stimulus (left ear clamp). In sham rats, DNIC were reproducibly recruited by a heterotopically applied conditioning stimulus, an effect that was absent in neuropathic rats. Intra-DRt naloxone had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. In addition, intra-DRt naloxone blocked DNIC in sham rats, but had no effect in SNL rats. Intra-ILC lidocaine had no effect on spinal neuronal responses to dynamic brush, punctate mechanical, evaporative cooling and heat stimuli in sham and SNL rats. However, differential effects were observed in relation to the expression of DNIC; intra-ILC lidocaine blocked activation of DNIC in sham rats but restored DNIC in SNL rats. These data suggest that the ILC is not directly involved in mediating DNIC but can modulate its activation and that DRt involvement in DNIC requires opioidergic signalling.

Modulation of sensitization processes in the management of pain and the importance of descending pathways: a role for tapentadol?

Objective: This paper presents and discusses recent evidence on the pathophysiological mechanisms of pain. The role of tapentadol - an analgesic molecule characterized by an innovative mechanism of action (i.e. µ-opioid receptor [MOR] agonism and inhibition of noradrenaline [NA] reuptake [NRI]) - in the modulation of pain, and the most recent pharmacological evidence on this molecule (e.g. the µ-load concept) are also presented and commented upon.Methods: Narrative review.Results: Solid evidence has highlighted the importance of central sensitization in the transition from acute to chronic pain. In particular, the noradrenergic system holds a major role in limiting central sensitization and the progression to chronic pain. Therefore, pharmacological modulation of the noradrenergic system appears to be a well-grounded strategy for the control of chronic pain. Tapentadol is characterized by a to-date-unique mechanism of action since it acts both as a MOR agonist and as an inhibitor of NA reuptake. The synergistic interaction of these two mechanisms allows a strong analgesic effect by acting on both ascending and descending pathways. Of note, the reduced µ-load of tapentadol has two important consequences: first, it limits the risk of opioid-related adverse events, as well as the risk of dependence; second, the NA component becomes predominant at least in some types of pain with consequent specific clinical efficacy in the treatment of neuropathic and chronic pain.Conclusions: According to these characteristics, tapentadol appears suitable in the treatment of chronic pain conditions characterized by both a nociceptive and a neuropathic component, such as osteoarthritis or back pain.

What goes up must come down: insights from studies on descending controls acting on spinal pain processing.

Descending controls link higher processing of noxious signals to modulation of spinal cord responses to their noxious inputs. It has become possible to study one key inhibitory system in animals and humans using one painful stimulus to attenuate another distant response and so eliciting diffuse noxious inhibitory controls (DNIC) or the human counterpart, conditioned pain modulation (CPM). Here, we discuss the neuronal pathways in both species, their pharmacology and examine changes in descending controls with a focus on osteoarthritis. We will also discuss the opposing descending facilitatory system. Strong parallels between DNIC and CPM emphasize the possibility of forward and reverse translation.

Selective modulation of tonic aversive qualities of neuropathic pain by morphine in the central nucleus of the amygdala requires endogenous opioid signaling in the anterior cingulate cortex.

The amygdala is a key subcortical region believed to contribute to emotional components of pain. As opioid receptors are found in both the central (CeA) and basolateral (BLA) nuclei of the amygdala, we investigated the effects of morphine microinjection on evoked pain responses, pain-motivated behaviors, dopamine release in the nucleus accumbens (NAc), and descending modulation in rats with left-side spinal nerve ligation (SNL). Morphine administered into the right or left CeA had no effect on nerve injury-induced tactile allodynia or mechanical hyperalgesia. Right, but not left, CeA morphine produced conditioned place preference (CPP) and increased extracellular dopamine in the NAc selectively in SNL rats, suggesting relief of aversive qualities of ongoing pain. In SNL rats, CPP and NAc dopamine release following right CeA morphine was abolished by blocking mu opioid receptor signaling in the rostral anterior cingulate cortex (rACC). Right CeA morphine also significantly restored SNL-induced loss of the diffuse noxious inhibitory controls, a spino-bulbo-spinal pain modulatory mechanism, termed conditioned pain modulation in humans. Microinjection of morphine into the BLA had no effects on evoked behaviors and did not produce CPP in nerve-injured rats. These findings demonstrate that the amygdalar action of morphine is specific to the right CeA contralateral to the side of injury and results in enhancement of net descending inhibition. In addition, engagement of mu opioid receptors in the right CeA modulates affective qualities of ongoing pain through endogenous opioid neurotransmission within the rACC, revealing opioid-dependent functional connections from the CeA to the rACC.