Increased Noradrenergic Neurotransmission to a Pain Facilitatory Area of the Brain Is Implicated in Facilitation of Chronic Pain

Martins, Isabel; Carvalho, Pedro; Vries, Martin G. de; Teixeira‐Pinto, Armando; Wilson, Steven P.; Westerink, Ben H.C.; Tavares, Isaura

doi:10.1097/aln.0000000000000749

Cited by 38 publications

(49 citation statements)

References 54 publications

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“…This implies the LC is a chronic pain generator. The results also concur with studies implying that with persisting trigeminal nociceptive input, the LC contributes to facilitation of mechanical hypersensitivity through both descending and ascending circuitry (Martins, et al, 2013; Martins et al, 2015). …”

Section: Discussionsupporting

confidence: 89%

“…LC neuronal activation indicated by increased expression of c-fos and pCREB after nerve ligation has been shown previously (Brightwell and Taylor, 2009; Martins et al, 2015). In further support of a facilitative function for ascending LC NA pathways during chronic neuropathic pain rather than the inhibitory function described in other acute pain models, we specifically performed pharmacological studies with NAα1 or NAα2 receptor antagonists to block NA signaling in the forebrain mPFC region.…”

Section: Discussionsupporting

confidence: 72%

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GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex

et al. 2016

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Trigeminal neuropathic pain is described as constant excruciating facial pain. The study goal was to investigate the role of nucleus locus coeruleus (LC) in a model of chronic orofacial neuropathic pain (CCI-ION). The study examines LC's relationship to both the medullary dorsal horn receiving trigeminal nerve sensory innervation and the medial prefrontal cortex (mPFC). LC is a major source of CNS noradrenaline (NA) and a primary nucleus involved in pain modulation. Although descending inhibition of acute pain by LC is well established, contribution of the LC to facilitation of chronic neuropathic pain is also reported. In the present study, a rat orofacial pain model of trigeminal neuropathy was induced by chronic constrictive injury of the infraorbital nerve (CCI-ION). Orofacial neuropathic pain was indicated by development of whisker pad mechanical hypersensitivity. Hypersensitivity was alleviated by selective elimination of NA neurons, including LC (A6 cell group), with the neurotoxin anti-dopamine-β-hydroxylase saporin (anti-DβH-saporin) microinjected either intracerebroventricularly (i.c.v.) or into trigeminal spinal nucleus caudalis (spVc). The GABA A receptor antagonist, bicuculline, administered directly into LC (week 8) inhibited hypersensitivity. This indicates a valence shift in which increased GABA A signaling ongoing in LC after trigeminal nerve injury paradoxically produces excitatory facilitation of the chronic pain state. Microinjection of NAα1 receptor antagonist, benoxathian, into mPFC attenuated whisker pad hypersensitivity, while NAα2 receptor antagonist, idazoxan, was ineffective. Thus, GABA A -mediated activation of NA neurons during CCI-ION can facilitate hypersensitivity through NAα1 receptors in the mPFC. These data indicate LC is a chronic pain generator. Published by Elsevier Ltd on behalf of IBRO.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 72%

GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex

et al. 2016

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“…Reducing noradrenaline release at the DRt by using a viral vector derived from the HSV-1 which selectively reduced noradrenaline synthesis in noradrenergic DRt afferents, significantly attenuated the behavioral manifestations of neuropathic pain for nearly 2 months (Martins et al, 2010). Our studies also show an impairment of the feedback inhibitory function of α 2 -adrenoreceptors at the DRt during neuropathic pain, which likely further contributes to enhance the noradrenergic input to the DRt during neuropathic pain (Martins et al, 2015b). The increased noradrenergic neurotransmission at the DRt, enhancing pain facilitation from this area, raises an important issue related to the treatment of neuropathic pain with antidepressants inhibiting noradrenaline reuptake.…”

Section: Chronic Pain As a Trigger Of Neuroplasticity At The Rvm-vlm-supporting

confidence: 56%

“…The recent studies performed by our group implicate the noradrenergic modulation of the DRt in the enhancement of DRt pain facilitation during neuropathic pain. We showed that nociceptive stimulation increased noradrenaline release at the DRt which enhanced pain facilitation from the DRt through activation of α 1 -adrenoreceptors (Martins et al, 2015b). Reducing noradrenaline release at the DRt by using a viral vector derived from the HSV-1 which selectively reduced noradrenaline synthesis in noradrenergic DRt afferents, significantly attenuated the behavioral manifestations of neuropathic pain for nearly 2 months (Martins et al, 2010).…”

Section: Chronic Pain As a Trigger Of Neuroplasticity At The Rvm-vlm-mentioning

confidence: 98%

“…Our recent functional studies show that the DRt acts as an important relay station in the mediation of descending facilitation from noradrenergic areas, namely the LC and A 5 noradrenergic groups (Martins et al, 2013). The LC exerts a bidirectional role on pain modulation (Hickey et al, 2014) and its pain facilitatory role is relayed by the DRt (Martins et al, 2010, 2013, 2015b). …”

Section: The Rvm-vlm-drt Triad As a Key Gateway For Top-down Pain Modmentioning

confidence: 99%

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Reticular Formation and Pain: The Past and the Future

Martins

Tavares

2017

Front. Neuroanat.

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The involvement of the reticular formation (RF) in the transmission and modulation of nociceptive information has been extensively studied. The brainstem RF contains several areas which are targeted by spinal cord afferents conveying nociceptive input. The arrival of nociceptive input to the RF may trigger alert reactions which generate a protective/defense reaction to pain. RF neurons located at the medulla oblongata and targeted by ascending nociceptive information are also involved in the control of vital functions that can be affected by pain, namely cardiovascular control. The RF contains centers that belong to the pain modulatory system, namely areas involved in bidirectional balance (decrease or enhancement) of pain responses. It is currently accepted that the imbalance of pain modulation towards pain facilitation accounts for chronic pain. The medullary RF has the peculiarity of harboring areas involved in bidirectional pain control namely by the existence of specific neuronal populations involved in antinociceptive or pronociceptive behavioral responses, namely at the rostroventromedial medulla (RVM) and the caudal ventrolateral medulla (VLM). Furthermore the dorsal reticular nucleus (also known as subnucleus reticularis dorsalis; DRt) may enhance nociceptive responses, through a reverberative circuit established with spinal lamina I neurons and inhibit wide-dynamic range (WDR) neurons of the deep dorsal horn. The components of the triad RVM-VLM-DRt are reciprocally connected and represent a key gateway for top-down pain modulation. The RVM-VLM-DRt triad also represents the neurobiological substrate for the emotional and cognitive modulation of pain, through pathways that involve the periaqueductal gray (PAG)-RVM connection. Collectively, we propose that the RVM-VLM-DRt triad represents a key component of the “dynamic pain connectome” with special features to provide integrated and rapid responses in situations which are life-threatening and involve pain. The new available techniques in neurobiological studies both in animal and human studies are producing new and fascinating data which allow to understand the complex role of the RF in pain modulation and its integration with several body functions and also how the RF accounts for chronic pain.

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The noradrenergic locus coeruleus as a chronic pain generator

Taylor

Westlund

2016

J of Neuroscience Research

104

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Central noradrenergic centers such as the locus coeruleus are traditionally viewed as pain inhibitory; however, complex interactions among brainstem pathways and their receptors modulate both inhibition and facilitation of pain. In addition to the well-described role of descending pontospinal pathways that inhibit spinal nociceptive transmission, an emerging body of research now indicates that noradrenergic neurons in the locus coeruleus (LC) and their terminals in the dorsal reticular nucleus (DRt), medial prefrontal cortex (mPFC), spinal dorsal horn and trigeminal spinal nucleus caudalis (spVc) participate in the development and maintenance of allodynia and hyperalgesia after nerve injury. With time after injury, we argue that the balance of LC function shifts from pain inhibition to pain facilitation. Thus, the pain inhibitory actions of antidepressant drugs achieved with elevated noradrenaline concentrations in the dorsal horn may be countered or even superseded by simultaneous activation of supraspinal facilitating systems dependent on α1-adrenoreceptor in the DRt and mPFC as well as α2-adrenoreceptors in the LC. Indeed, these opposing actions may account in part for the limited treatment efficacy of tricyclic antidepressants and noradrenaline reuptake inhibitors such as duloxetine for the treatment of chronic pain. We propose that the traditional view of the LC as a pain inhibitory structure be modified to account for its capacity as a pain facilitator. Future studies are needed to determine the neurobiology of ascending and descending pathways and the pharmacology of receptors underlying LC-mediated pain inhibition and facilitation.

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Increased Noradrenergic Neurotransmission to a Pain Facilitatory Area of the Brain Is Implicated in Facilitation of Chronic Pain

Abstract: Chronic pain induces brainstem noradrenergic activation that enhances descending facilitation from the DRt. This suggests that antidepressants inhibiting noradrenaline reuptake may enhance pain facilitation from the brain, counteracting their analgesic effects at the spinal cord.

Cited by 38 publications

References 54 publications

GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex

GABA-A receptor activity in the noradrenergic locus coeruleus drives trigeminal neuropathic pain in the rat; contribution of NAα1 receptors in the medial prefrontal cortex

Reticular Formation and Pain: The Past and the Future

The noradrenergic locus coeruleus as a chronic pain generator

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