Unilateral hindpaw inflammation induces bilateral activation of the locus coeruleus and the nucleus subcoeruleus in the rat

Tsuruoka, Masayoshi; Arai, Young‐Chang P.; Nomura, Hajime; Matsutani, Kiyo; Willis, William D.

doi:10.1016/s0361-9230(03)00099-6

Cited by 37 publications

(31 citation statements)

References 44 publications

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“…This extends previous reports indicating that unilateral high intensity nerve stimulation (Voisin et al, 2005), paw inflammation with carrageenan (Tsuruoka et al, 2003a), intraplantar formalin (Palkovits et al, 1999), or CCI (Mao et al, 1993) increased LC Fos and/or neuronal activity in a bilateral pattern. This is not surprising since spinal projection neurons not only decussate and travel to the contralateral side of the brain, but also ascend bilaterally (Spike et al, 2003).…”

Section: Discussionsupporting

confidence: 90%

Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain

Brightwell

Taylor²

2009

Neuroscience

102

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Current theories of neuropathic hypersensitivity include an imbalance of supraspinal inhibition and facilitation. Our overall hypothesis is that the locus coeruleus (LC), classically interpreted as a source of pain inhibition, may paradoxically result in facilitation after tibial and common peroneal nerve transection (spared sural nerve injury – SNI). We first tested the hypothesis that non-noxious tactile hindpaw stimulation of the spared sural innervation territory increases neuronal activity in the LC in male rats. We observed a bilateral increase in the stimulus-evoked expression of transcription factors Fos and phosphorylated CREB (pCREB) in LC after SNI but not sham surgery; these markers of neuronal activity correlated with the intensity of tactile allodynia. We next tested the hypothesis that noradrenergic neurons contribute to the development of neuropathic pain. To selectively destroy these neurons, we delivered anti-dopamine-β-hydroxylase saporin (anti-DβH-saporin) into the intracerebroventricular space two weeks before SNI. We found that anti-DβH-saporin, but not an IgG-saporin control, reduced behavioural signs of tactile allodynia, mechanical hyperalgesia, and cold allodynia from 3-28 d after SNI. Our final experiment tested the hypothesis that the LC contributes to the maintenance of neuropathic pain. We performed SNI, waited two weeks for maximal allodynia and hyperalgesia to develop, and then administered the local anaesthetic lidocaine (4%) directly into the LC parenchyma. Lidocaine reduced all behavioural signs of neuropathic pain in a reversible manner, suggesting that the LC contributes to pain facilitation. We conclude that, in addition to its well-known inhibition of acute and inflammatory pain, the LC facilitates the development and maintenance of neuropathic pain in the SNI model. Further studies are needed to determine the facilitatory pathways emanating from the LC.

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Section: Discussionsupporting

confidence: 90%

Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain

Brightwell

Taylor²

2009

Neuroscience

102

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“…While this extensive NE network influences a large number of brain functions, it is the descending coeruleospinal pathway that plays an important role in the endogenous pain inhibitory system. 23,25,26 We have demonstrated that a single DBV injection into the Zusanli acupoint effectively activates brainstem catecholaminergic neurons in the LC and that this activation underlies DBV-induced antinociception. 13,20,29 We have also shown that blockade of spinal alpha-2 adrenoceptors reversed BV's antinociceptive effect in both acute and chronic pain models, indicating that descending NE projections are critical to BV's antinociceptive effect.…”

Section: Discussionmentioning

confidence: 99%

Repetitive Treatment With Diluted Bee Venom Reduces Neuropathic Pain Via Potentiation of Locus Coeruleus Noradrenergic Neuronal Activity and Modulation of Spinal NR1 Phosphorylation in Rats

Kang¹,

Roh²,

Yoon³

et al. 2012

The Journal of Pain

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“…Via these modulatory pathways, the LC exerts an inhibitory influence on pain sensation [(Maeda et al, 2009) (hind paw inflammation)]; for reviews see Willis and Westlund (1997); Pertovaara and Almeida (2006); Ossipov et al (2010). The LC can be activated by noxious stimulation (see above), which leads to the inhibition of the pain evoked by a noxious stimulus, such as hind paw inflammation (Tsuruoka et al, 2003a; Maeda et al, 2009). LC activation by direct electrical stimulation also evokes an anti-nociceptive effect [Margalit and Segal, 1979 (hot plate); West et al, 1993 (noxious heat: foot withdrawal response)].…”

Section: Modulation Of Pain By the Lcmentioning

confidence: 99%

Modulation of physiological reflexes by pain: role of the locus coeruleus

Szabadi

2012

Front. Integr. Neurosci.

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The locus coeruleus (LC) is activated by noxious stimuli, and this activation leads to inhibition of perceived pain. As two physiological reflexes, the acoustic startle reflex and the pupillary light reflex, are sensitive to noxious stimuli, this review considers evidence that this sensitivity, at least to some extent, is mediated by the LC. The acoustic startle reflex, contraction of a large body of skeletal muscles in response to a sudden loud acoustic stimulus, can be enhanced by both directly (“sensitization”) and indirectly (“fear conditioning”) applied noxious stimuli. Fear-conditioning involves the association of a noxious (unconditioned) stimulus with a neutral (conditioned) stimulus (e.g., light), leading to the ability of the conditioned stimulus to evoke the “pain response”. The enhancement of the startle response by conditioned fear (“fear-potentiated startle”) involves the activation of the amygdala. The LC may also be involved in both sensitization and fear potentiation: pain signals activate the LC both directly and indirectly via the amygdala, which results in enhanced motoneurone activity, leading to an enhanced muscular response. Pupil diameter is under dual sympathetic/parasympathetic control, the sympathetic (noradrenergic) output dilating, and the parasympathetic (cholinergic) output constricting the pupil. The light reflex (constriction of the pupil in response to a light stimulus) operates via the parasympathetic output. The LC exerts a dual influence on pupillary control: it contributes to the sympathetic outflow and attenuates the parasympathetic output by inhibiting the Edinger-Westphal nucleus, the preganglionic cholinergic nucleus in the light reflex pathway. Noxious stimulation results in pupil dilation (“reflex dilation”), without any change in the light reflex response, consistent with sympathetic activation via the LC. Conditioned fear, on the other hand, results in the attenuation of the light reflex response (“fear-inhibited light reflex”), consistent with the inhibition of the parasympathetic light reflex via the LC. It is suggested that directly applied pain and fear-conditioning may affect different populations of autonomic neurones in the LC, directly applied pain activating sympathetic and fear-conditioning parasympathetic premotor neurones.

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Unilateral hindpaw inflammation induces bilateral activation of the locus coeruleus and the nucleus subcoeruleus in the rat

Cited by 37 publications

References 44 publications

Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain

Noradrenergic neurons in the locus coeruleus contribute to neuropathic pain

Repetitive Treatment With Diluted Bee Venom Reduces Neuropathic Pain Via Potentiation of Locus Coeruleus Noradrenergic Neuronal Activity and Modulation of Spinal NR1 Phosphorylation in Rats

Modulation of physiological reflexes by pain: role of the locus coeruleus

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