Transition to chronic pain: opportunities for novel therapeutics

Price, Theodore J.; Basbaum, Allan I.; Bresnahan, Jacqueline C.; Chambers, Jan F.; Koninck, Yves De; Edwards, Robert R.; Ji, Ru-Rong; Katz, Joel; Kavelaars, Annemieke; Levine, Jon D.; Porter, Linda; Schechter, Neil L.; Sluka, Kathleen A.; Terman, Gregory W.; Wager, Tor D.; Yaksh, Tony L.; Dworkin, Robert H.

doi:10.1038/s41583-018-0012-5

Cited by 121 publications

(111 citation statements)

References 6 publications

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“…Taken together, our findings demonstrate a hitherto unknown pathway of pain regulation, involving two key structures associated primarily with the affective aspects of chronic pain, the parabrachial complex and the amygdala. Because the affective component of chronic pain is the component most directly associated with patients' suffering, and is the component most resistant to treatment (Han et al, 2015;Neugebauer, 2015;Price et al, 2018;Corder et al, 2019), the identification of a novel pathway mediating this function may be directly relevant to planning novel therapies for this devastating condition.…”

Section: The Cea-pb Pathwaymentioning

confidence: 99%

An amygdalo-parabrachial pathway regulates pain perception and chronic pain

Raver

Uddin

et al. 2020

Preprint

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The parabrachial (PB) complex mediates both ascending nociceptive signaling and descending pain modulatory information in the affective/emotional pain pathway. We have recently reported that chronic pain is associated with amplified activity of PB neurons in a rat model of neuropathic pain. Here we demonstrate that similar activity amplification occurs in mice, and that this is related to suppressed inhibition to PB neurons from the central nucleus of the amygdala (CeA). Animals with pain after chronic constriction injury of the infraorbital nerve (CCI-Pain) displayed higher spontaneous and evoked activity in PB neurons, and a dramatic increase in afterdischarges-responses that far outlast the stimulus-compared to controls. PB neurons in CCI-Pain animals showed a reduction in inhibitory, GABAergic inputs. We show that-in both rats and mice-PB contains few GABAergic neurons, and that most of its GABAergic inputs arise from CeA. These CeA GABA neurons express dynorphin, somatostatin and/or corticotropin releasing hormone. We find that the efficacy of this CeA-LPB pathway is suppressed in chronic pain. Further, optogenetically stimulating this pathway suppresses acute pain, and inhibiting it, in naïve animals, evokes pain behaviors. These findings demonstrate that the CeA-LPB pathway is critically involved in pain regulation, and in the pathogenesis of chronic pain.We describe a novel pathway, consisting of inhibition by dynorphin, somatostatin and corticotropin-releasing hormone expressing neurons in the central nucleus of the amygdala that project to the parabrachial nucleus (PB). We show that this pathway regulates the activity of pain-related neurons in PB, and that, in chronic pain, this inhibitory pathway is suppressed, and that this suppression is causally related to pain perception. We propose that this amygdalo-parabrachial pathway is a key regulator of both chronic and acute pain, and a novel target for pain relief.

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Section: The Cea-pb Pathwaymentioning

confidence: 99%

An amygdalo-parabrachial pathway regulates pain perception and chronic pain

Raver

Uddin

et al. 2020

Preprint

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“…">IntroductionJoint inflammatory pain is a highly prevalent condition [1,2], and the available treatments are often inefficient and have various adverse side-effects [3]. The pathophysiological mechanisms underlying pain, in these chronic conditions, are still not completely understood [4][5][6][7][8].Chronic pain involves many different complex processes in key spinal and supraspinal areas, which may suffer significant changes in an attempt to adapt to the ongoing noxious stimuli [4,5,7]. Indeed, the control of pain implies several molecular changes at the spinal cord, in the descending modulation of pain, and in supraspinal areas involved in the emotional component of pain processing [4,5,7,[9][10][11].…”

mentioning

confidence: 99%

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

Pereira-Silva

Costa‐Pereira

Alonso

et al. 2020

IJMS

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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. IntroductionJoint inflammatory pain is a highly prevalent condition [1,2], and the available treatments are often inefficient and have various adverse side-effects [3]. The pathophysiological mechanisms underlying pain, in these chronic conditions, are still not completely understood [4][5][6][7][8].Chronic pain involves many different complex processes in key spinal and supraspinal areas, which may suffer significant changes in an attempt to adapt to the ongoing noxious stimuli [4,5,7]. Indeed, the control of pain implies several molecular changes at the spinal cord, in the descending modulation of pain, and in supraspinal areas involved in the emotional component of pain processing [4,5,7,[9][10][11]. The latter may be influenced and altered by the noxious stimuli and also may be responsible for changes in the way these pathologic stimuli are processed [9,12,13]. Despite this knowledge, much is still unclear about how and when these changes in pain processing occur during the progression of a chronic joint inflammatory painful condition. Indeed, the balance between facilitatory and inhibitory input is compromised in chronic pain [4,14]. Through the release of noradrenaline at the spinal cord, the descending noradrenergic system is implicated in the spinal inhibition of noxious input, modulating the transmission of nociceptive information [4,15]. This descending noradrenergic input is impaired in neuropathic pain conditions [16][17][18]. Although in joint inflammatory pain this is rather unexplored, the few studies performed suggest the presence of changes in this modulatory syste...

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“…It is generally accepted that altered somatosensory and nociceptive perception in neuropathic pain result from still incompletely understood changes at the dorsal horn circuitry [50][51][52]. Several of the suspected changes occur in second order intrinsic dorsal horn neurons.…”

Section: No Overt Changes In the Translatome Of Spinal Neurons After mentioning

confidence: 99%

Neuron Type-Specific Translatomes in Spinal Cords of Naïve and Neuropathic Mice

Gupta

Scheurer

Pelczar

et al. 2020

Preprint

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The spinal dorsal horn harbors a sophisticated and heterogeneous network of excitatory and inhibitory neurons that process peripheral signals encoding different sensory modalities. Although it has long been recognized that this network is crucial both for the separation and the integration of sensory signals of different modalities, the molecular identity of the underlying neurons and signaling mechanisms are still only partially understood. Here, we have used the translating ribosome affinity purification (TRAP) technique to map the translatomes of excitatory glutamatergic (VGLUT2 + ) and inhibitory GABA and/or glycinergic (VGAT + or Gad67 + ) neurons of the mouse spinal cord. Our analyses demonstrate that inhibitory and excitatory neurons are primarily set apart by the expression of genes encoding transcription factors or genes related to the production, release or re-uptake of their principal neurotransmitters (glutamate, GABA or glycine). Subsequent gene ontology (GO) term analyses revealed that neuropeptide signaling-related GO terms were highly enriched in the excitatory population. Eleven neuropeptide genes displayed largely non-overlapping expression patterns closely adhering to the laminar and hence also functional organization of the spinal cord grey matter, suggesting that they may serve as major determinants of modality-specific processing. Since this modality-specific processing of sensory input is severely compromised in chronic, especially neuropathic, pain, we also investigated whether peripheral nerve damage changes the neuron typespecific translatome. In summary, our results suggest that neuropeptides contribute to modalityspecific sensory processing in the spinal cord but also indicate that altered sensory encoding in neuropathic pain states occurs independent of major translatome changes in the spinal neurons.The ability to sense and discriminate different noxious and innocuous somatosensory stimuli is essential for all higher animals and humans in order to react adequately to external stimuli and internal conditions [1,2]. The spinal dorsal horn, i.e., the sensory part of the spinal cord, constitutes a key element in this process. It receives somatosensory signals from peripheral neurons and processes these signals together with other inputs descending from supraspinal sites in a complex network of inhibitory and excitatory interneurons before relaying these signals via projection neurons to supraspinal centers [3]. Projection neurons make up less than 10% of all dorsal horn neurons, while more than 90% of the neuronal population are interneurons of which, between 60 and 70% are excitatory glutamatergic neurons, and the rest is inhibitory (GABA and/or glycinergic).The spinal cord is organized in a laminar fashion, which has initially been proposed on the basis of differences in cell density and morphology between the different laminae [4, 5] but has later been shown to also reflect functional organization. This is especially reflected for example by the lamina specific innervation pattern by ...

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Transition to chronic pain: opportunities for novel therapeutics

Cited by 121 publications

References 6 publications

An amygdalo-parabrachial pathway regulates pain perception and chronic pain

An amygdalo-parabrachial pathway regulates pain perception and chronic pain

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

Neuron Type-Specific Translatomes in Spinal Cords of Naïve and Neuropathic Mice

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