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Chronic Pain: Spinal and Sovraspinal Neuroinflammation and Associated Negative Affective States

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 55695

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Prof. Dr. Sabatino Maione

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Department of Experimental Medicine, Division of Pharmacology, University of Campania “L. Vanvitelli”, 80138 Naples, Italy
Interests: pain; neuropsychopharmacology; neuroplasticity; neuroinflammation; endocannabinoids; glutamate

Dr. Danilo De Gregorio

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Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, QC, Canada
Interests: depression; anxiety; pain; europsychopharmacology; endocannabinoids; serotonin

Dr. Francesca Guida

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University of Campania “L. Vanvitelli”, Department of Experimental Medicine, Naples, Italy
Interests: pain; neuroinflammation; glia; neuropharmacology

Special Issue Information

Dear Colleagues,

The scope of the Special Issue would be the evaluation of the reciprocal relationship existing between pain and negative affective states (i.e., the forebrain pain mechanisms) and, in particular, the highlighting of the most advanced knowledge that underlies some long-term functional changes in limbic structures (i.e., prefrontal cortex, amygdala, DR, and PAG). Moreover, a relevant aspect that should emerge from this Special Issue should be the highlighting of the cross talk between the classic neurotransmitters and neuromodulators (i.e., neuropeptides, glutamate, GABA, NO, and neurotrophic factors) with several other molecules of more recent identification (i.e., endocannabinoids, prostamides, etc.) that are able to work synergistically or in opposition in supporting the limbic system neural plasticity induced by chronic pain and the complex and unpredictable central sequelae. A further important topic to consider will be the emerging targets for reversing such abnormal activity in these neural circuitries may contribute to pain relief and to improve some negative affective states.

Prof. Dr. Sabatino Maione
Dr. Danilo De Gregorio
Dr. Francesca Guida
Guest Editors

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Keywords

chronic pain
neuroinflammation
microglia
neural sensitization
spinal cord
forebrain
anxiety
depression
cognitive impairment

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Published Papers (9 papers)

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Research

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14 pages, 1617 KiB

Open AccessArticle

Paclitaxel Induces Upregulation of Transient Receptor Potential Vanilloid 1 Expression in the Rat Spinal Cord

by Yukako Kamata, Toshie Kambe, Terumasa Chiba, Ken Yamamoto, Kazuyoshi Kawakami, Kenji Abe and Kyoji Taguchi

Int. J. Mol. Sci. 2020, 21(12), 4341; https://doi.org/10.3390/ijms21124341 - 18 Jun 2020

Cited by 24 | Viewed by 3512

Abstract

Painful peripheral neuropathy is a common adverse effect of paclitaxel (PTX) treatment. To analyze the contribution of transient receptor potential vanilloid 1 (TRPV1) in the development of PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia, TRPV1 expression in the rat spinal cord was analyzed after intraperitoneal administration of 2 and 4 mg/kg PTX. PTX treatment increased the expression of TRPV1 protein in the spinal cord. Immunohistochemistry showed that PTX (4 mg/kg) treatment increased TRPV1 protein expression in the superficial layers of the spinal dorsal horn 14 days after treatment. Behavioral assessment using the paw withdrawal response showed that PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia after 14 days was significantly inhibited by oral or intrathecal administration of the TRPV1 antagonist AMG9810. We found that intrathecal administration of small interfering RNA (siRNA) to knock down TRPV1 protein expression in the spinal cord significantly decreased PTX-induced mechanical allodynia/hyperalgesia and thermal hyperalgesia. Together, these results demonstrate that TRPV1 receptor expression in spinal cord contributes, at least in part, to the development of PTX-induced painful peripheral neuropathy. TRPV1 receptor antagonists may be useful in the prevention and treatment of PTX-induced peripheral neuropathic pain. Full article

(This article belongs to the Special Issue Chronic Pain: Spinal and Sovraspinal Neuroinflammation and Associated Negative Affective States)

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28 pages, 3239 KiB

Open AccessArticle

Attenuation of the Diffuse Noxious Inhibitory Controls in Chronic Joint Inflammatory Pain Is Accompanied by Anxiodepressive-Like Behaviors and Impairment of the Descending Noradrenergic Modulation

by Raquel Pereira-Silva, José Tiago Costa-Pereira, Raquel Alonso, Paula Serrão, Isabel Martins and Fani L. Neto

Int. J. Mol. Sci. 2020, 21(8), 2973; https://doi.org/10.3390/ijms21082973 - 23 Apr 2020

Cited by 13 | Viewed by 3651

Abstract

The noradrenergic system is paramount for controlling pain and emotions. We aimed at understanding the descending noradrenergic modulatory mechanisms in joint inflammatory pain and its correlation with the diffuse noxious inhibitory controls (DNICs) and with the onset of anxiodepressive behaviours. In the complete Freund’s adjuvant rat model of Monoarthritis, nociceptive behaviors, DNICs, and anxiodepressive-like behaviors were evaluated. Spinal alpha2-adrenergic receptors (a2-AR), dopamine beta-hydroxylase (DBH), and noradrenaline were quantified concomitantly with a2-AR pharmacologic studies. The phosphorylated extracellular signal–regulated kinases 1 and 2 (pERK1/2) were quantified in the Locus coeruleus (LC), amygdala, and anterior cingulate cortex (ACC). DNIC was attenuated at 42 days of monoarthritis while present on days 7 and 28. On day 42, in contrast to day 28, noradrenaline was reduced and DBH labelling was increased. Moreover, spinal a2-AR were potentiated and no changes in a2-AR levels were observed. Additionally, at 42 days, the activation of ERKs1/2 was increased in the LC, ACC, and basolateral amygdala. This was accompanied by anxiety- and depressive-like behaviors, while at 28 days, only anxiety-like behaviors were observed. The data suggest DNIC is attenuated in prolonged chronic joint inflammatory pain, and this is accompanied by impairment of the descending noradrenergic modulation and anxiodepressive-like behaviors. Full article

(This article belongs to the Special Issue Chronic Pain: Spinal and Sovraspinal Neuroinflammation and Associated Negative Affective States)

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19 pages, 3378 KiB

Open AccessArticle

Suppression of Superficial Microglial Activation by Spinal Cord Stimulation Attenuates Neuropathic Pain Following Sciatic Nerve Injury in Rats

by Masamichi Shinoda, Satoshi Fujita, Shiori Sugawara, Sayaka Asano, Ryo Koyama, Shintaro Fujiwara, Kumi Soma, Takaaki Tamagawa, Tomoyuki Matsui, Daisuke Ikutame, Masatoshi Ando, Ayaka Osada, Yuki Kimura, Kazutaka Kobayashi, Takamitsu Yamamoto, Kuniko Kusama-Eguchi, Masayuki Kobayashi, Yoshinori Hayashi and Koichi Iwata

Int. J. Mol. Sci. 2020, 21(7), 2390; https://doi.org/10.3390/ijms21072390 - 30 Mar 2020

Cited by 12 | Viewed by 3939

Abstract

We evaluated the mechanisms underlying the spinal cord stimulation (SCS)-induced analgesic effect on neuropathic pain following spared nerve injury (SNI). On day 3 after SNI, SCS was performed for 6 h by using electrodes paraspinally placed on the L4-S1 spinal cord. The effects of SCS and intraperitoneal minocycline administration on plantar mechanical sensitivity, microglial activation, and neuronal excitability in the L4 dorsal horn were assessed on day 3 after SNI. The somatosensory cortical responses to electrical stimulation of the hind paw on day 3 following SNI were examined by using in vivo optical imaging with a voltage-sensitive dye. On day 3 after SNI, plantar mechanical hypersensitivity and enhanced microglial activation were suppressed by minocycline or SCS, and L4 dorsal horn nociceptive neuronal hyperexcitability was suppressed by SCS. In vivo optical imaging also revealed that electrical stimulation of the hind paw-activated areas in the somatosensory cortex was decreased by SCS. The present findings suggest that SCS could suppress plantar SNI-induced neuropathic pain via inhibition of microglial activation in the L4 dorsal horn, which is involved in spinal neuronal hyperexcitability. SCS is likely to be a potential alternative and complementary medicine therapy to alleviate neuropathic pain following nerve injury. Full article

(This article belongs to the Special Issue Chronic Pain: Spinal and Sovraspinal Neuroinflammation and Associated Negative Affective States)

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20 pages, 4772 KiB

Open AccessArticle

Evans Blue Reduces Neuropathic Pain Behavior by Inhibiting Spinal ATP Release

by Yuhua Yin, Jinpyo Hong, Thuỳ Linh Phạm, Juhee Shin, Do Hyeong Gwon, Hyeok Hee Kwon, Nara Shin, Hyo Jung Shin, Sun Yeul Lee, Won-hyung Lee and Dong Woon Kim

Int. J. Mol. Sci. 2019, 20(18), 4443; https://doi.org/10.3390/ijms20184443 - 9 Sep 2019

Cited by 14 | Viewed by 4258

Abstract

Upon peripheral nerve injury, vesicular ATP is released from damaged primary afferent neurons. This extracellular ATP subsequently activates purinergic receptors of the spinal cord, which play a critical role in neuropathic pain. As an inhibitor of the vesicular nucleotide transporter (VNUT), Evans blue (EB) inhibits the vesicular storage and release of ATP in neurons. Thus, we tested whether EB could attenuate neuropathic pain behavior induced by spinal nerve ligation (SNL) in rats by targeting VNUT. An intrathecal injection of EB efficiently attenuated mechanical allodynia for five days in a dose-dependent manner and enhanced locomotive activity in an SNL rat model. Immunohistochemical analysis showed that EB was found in VNUT immunoreactivity on neurons in the dorsal root ganglion and the spinal dorsal horn. The level of ATP in cerebrospinal fluid in rats with SNL-induced neuropathic pain decreased upon administration of EB. Interestingly, EB blocked ATP release from neurons, but not glial cells in vitro. Eventually, the loss of ATP decreased microglial activity in the ipsilateral dorsal horn of the spinal cord, followed by a reduction in reactive oxygen species and proinflammatory mediators, such as interleukin (IL)-1β and IL-6. Finally, a similar analgesic effect of EB was demonstrated in rats with monoiodoacetate-induced osteoarthritis (OA) pain. Taken together, these data demonstrate that EB prevents ATP release in the spinal dorsal horn and reduces the ATP/purinergic receptor-induced activation of spinal microglia followed by a decline in algogenic substances, thereby relieving neuropathic pain in rats with SNL. Full article

(This article belongs to the Special Issue Chronic Pain: Spinal and Sovraspinal Neuroinflammation and Associated Negative Affective States)

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18 pages, 1432 KiB

Open AccessArticle

Contribution of Corticotropin-Releasing Factor Receptor 1 (CRF1) to Serotonin Receptor 5-HT_2CR Function in Amygdala Neurons in a Neuropathic Pain Model

by Guangchen Ji and Volker Neugebauer

Int. J. Mol. Sci. 2019, 20(18), 4380; https://doi.org/10.3390/ijms20184380 - 6 Sep 2019

Cited by 18 | Viewed by 3062

Abstract

The amygdala plays a key role in emotional-affective aspects of pain and in pain modulation. The central nucleus (CeA) serves major amygdala output functions related to emotional-affective behaviors and pain modulation. Our previous studies implicated the corticotropin-releasing factor (CRF) system in amygdala plasticity and pain behaviors in an arthritis model. We also showed that serotonin (5-HT) receptor subtype 5-HT_2CR in the basolateral amygdala (BLA) contributes to increased CeA output and neuropathic pain-like behaviors. Here, we tested the novel hypothesis that 5-HT_2CR in the BLA drives CRF1 receptor activation to increase CeA neuronal activity in neuropathic pain. Extracellular single-unit recordings of CeA neurons in anesthetized adult male rats detected increased activity in neuropathic rats (spinal nerve ligation model) compared to sham controls. Increased CeA activity was blocked by local knockdown or pharmacological blockade of 5-HT_2CR in the BLA, using stereotaxic administration of 5-HT_2CR short hairpin RNA (shRNA) viral vector or a 5-HT_2CR antagonist (SB242084), respectively. Stereotaxic administration of a CRF1 receptor antagonist (NBI27914) into the BLA also decreased CeA activity in neuropathic rats and blocked the facilitatory effects of a 5-HT_2CR agonist (WAY161503) administered stereotaxically into the BLA. Conversely, local (BLA) knockdown of 5-HT_2CR eliminated the inhibitory effect of NBI27914 and the facilitatory effect of WAY161503 in neuropathic rats. The data suggest that 5-HT_2CR activation in the BLA contributes to neuropathic pain-related amygdala (CeA) activity by engaging CRF1 receptor signaling. Full article

(This article belongs to the Special Issue Chronic Pain: Spinal and Sovraspinal Neuroinflammation and Associated Negative Affective States)

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15 pages, 1456 KiB

Open AccessArticle

Metabotropic Glutamate Receptor 5 and 8 Modulate the Ameliorative Effect of Ultramicronized Palmitoylethanolamide on Cognitive Decline Associated with Neuropathic Pain

by Serena Boccella, Ida Marabese, Monica Iannotta, Carmela Belardo, Volker Neugebauer, Mariacristina Mazzitelli, Gorizio Pieretti, Sabatino Maione and Enza Palazzo

Int. J. Mol. Sci. 2019, 20(7), 1757; https://doi.org/10.3390/ijms20071757 - 9 Apr 2019

Cited by 17 | Viewed by 3852

Abstract

This study investigated whether metabotropic glutamate receptor (mGluR) 5 and 8 are involved in the effect of ultramicronizedpalmitoylethanolamide (um-PEA) on the cognitive behavior and long term potentiation (LTP) at entorhinal cortex (LEC)-dentate gyrus (DG) pathway in mice rendered neuropathic by the spare nerve injury (SNI). SNI reduced discriminative memory and LTP. Um-PEA treatment started after the development of neuropathic pain had no effects in sham mice, whereas it restored cognitive behavior and LTP in SNI mice. 2-Methyl-6-(phenylethynyl) pyridine (MPEP), a selective mGluR5 antagonist, improved cognition in SNI mice and produced a chemical long term depression of the field excitatory postsynaptic potentials (fEPSPs) in sham and SNI mice. After theta burst stimulation (TBS) MPEP restored LTP in SNI mice. In combination with PEA, MPEP antagonized the PEA effect on discriminative memory and decreased LTP in SNI mice. The (RS)-4-(1-amino-1-carboxyethyl)phthalic acid (MDCPG), a selective mGluR8 antagonist, did not affect discriminative memory, but it induced a chemical LTP and prevented the enhancement of fEPSPs after TBS in SNI mice which were treated or not treated with PEA. The effect of PEA on LTP and cognitive behavior was modulated by mGluR5 and mGluR8. In particular in the SNI conditions, the mGluR5 blockade facilitated memory and LTP, but prevented the beneficial effects of PEA on discriminative memory while the mGluR8 blockade, which was ineffective in itself, prevented the favorable action of the PEA on LTP. Thus, although their opposite roles (excitatory/inhibitory of the two receptor subtypes on the glutamatergic system), they appeared to be required for the neuroprotective effect of PEA in conditions of neuropathic pain. Full article

(This article belongs to the Special Issue Chronic Pain: Spinal and Sovraspinal Neuroinflammation and Associated Negative Affective States)

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Review

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21 pages, 966 KiB

Open AccessReview

Behavioral, Biochemical and Electrophysiological Changes in Spared Nerve Injury Model of Neuropathic Pain

by Francesca Guida, Danilo De Gregorio, Enza Palazzo, Flavia Ricciardi, Serena Boccella, Carmela Belardo, Monica Iannotta, Rosmara Infantino, Federica Formato, Ida Marabese, Livio Luongo, Vito de Novellis and Sabatino Maione

Int. J. Mol. Sci. 2020, 21(9), 3396; https://doi.org/10.3390/ijms21093396 - 11 May 2020

Cited by 77 | Viewed by 9312

Abstract

Neuropathic pain is a pathological condition induced by a lesion or disease affecting the somatosensory system, with symptoms like allodynia and hyperalgesia. It has a multifaceted pathogenesis as it implicates several molecular signaling pathways involving peripheral and central nervous systems. Affective and cognitive dysfunctions have been reported as comorbidities of neuropathic pain states, supporting the notion that pain and mood disorders share some common pathogenetic mechanisms. The understanding of these pathophysiological mechanisms requires the development of animal models mimicking, as far as possible, clinical neuropathic pain symptoms. Among them, the Spared Nerve Injury (SNI) model has been largely characterized in terms of behavioral and functional alterations. This model is associated with changes in neuronal firing activity at spinal and supraspinal levels, and induces late neuropsychiatric disorders (such as anxious-like and depressive-like behaviors, and cognitive impairments) comparable to an advanced phase of neuropathy. The goal of this review is to summarize current findings in preclinical research, employing the SNI model as a tool for identifying pathophysiological mechanisms of neuropathic pain and testing pharmacological agent. Full article

(This article belongs to the Special Issue Chronic Pain: Spinal and Sovraspinal Neuroinflammation and Associated Negative Affective States)

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13 pages, 258 KiB

Open AccessReview

Modulation of the Negative Affective Dimension of Pain: Focus on Selected Neuropeptidergic System Contributions

by Francesca Felicia Caputi, Laura Rullo, Serena Stamatakos, Sanzio Candeletti and Patrizia Romualdi

Int. J. Mol. Sci. 2019, 20(16), 4010; https://doi.org/10.3390/ijms20164010 - 17 Aug 2019

Cited by 9 | Viewed by 3175

Abstract

It is well known that emotions can interfere with the perception of physical pain, as well as with the development and maintenance of painful conditions. On the other hand, somatic pain can have significant consequences on an individual’s affective behavior. Indeed, pain is defined as a complex and multidimensional experience, which includes both sensory and emotional components, thus exhibiting the features of a highly subjective experience. Over the years, neural pathways involved in the modulation of the different components of pain have been identified, indicating the existence of medial and lateral pain systems, which, respectively, project from medial or lateral thalamic nuclei to reach distinct cortex regions relating to specific functions. However, owing to the limited information concerning how mood state and painful input affect each other, pain treatment is frequently unsatisfactory. Different neuromodulators, including endogenous neuropeptides, appear to be involved in pain-related emotion and in its affective influence on pain perception, thus playing key roles in vulnerability and clinical outcome. Hence, this review article focuses on evidence concerning the modulation of the sensory and affective dimensions of pain, with particular attention given to some selected neuropeptidergic system contributions. Full article

(This article belongs to the Special Issue Chronic Pain: Spinal and Sovraspinal Neuroinflammation and Associated Negative Affective States)

17 pages, 441 KiB

Open AccessReview

Chronic Pain: Structural and Functional Changes in Brain Structures and Associated Negative Affective States

by Seoyon Yang and Min Cheol Chang

Int. J. Mol. Sci. 2019, 20(13), 3130; https://doi.org/10.3390/ijms20133130 - 26 Jun 2019

Cited by 204 | Viewed by 20182

Abstract

Chronic pain is a condition in which pain progresses from an acute to chronic state and persists beyond the healing process. Chronic pain impairs function and decreases patients’ quality of life. In recent years, efforts have been made to deepen our understanding of chronic pain and to develop better treatments to alleviate chronic pain. In this review, we summarize the results of previous studies, focusing on the mechanisms underlying chronic pain development and the identification of neural areas related to chronic pain. We review the association between chronic pain and negative affective states. Further, we describe the structural and functional changes in brain structures that accompany the chronification of pain and discuss various neurotransmitter families involved. Our review aims to provide guidance for the development of future therapeutic approaches that could be used in the management of chronic pain. Full article

(This article belongs to the Special Issue Chronic Pain: Spinal and Sovraspinal Neuroinflammation and Associated Negative Affective States)

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