Research ReportActivation of ERK in the locus coeruleus following acute noxious stimulation
Introduction
The locus coeruleus (LC) in the dorsolateral pons sends noradrenergic projection to the spinal dorsal horn and is a critical component of the descending pain modulatory system. Electrical or chemical stimulation of the LC produces release of noradrenaline (NA) in the spinal cord (Hentall et al., 2003), inhibits the responses of spinal dorsal horn neurons to noxious stimuli (Jones and Gebhart, 1986, Mokha et al., 1985) and induces antinociception (West et al., 1993). Noxious stimuli activate the LC neurons, which is evidenced by Fos expression, a measure of neural activation, in the previous studies (Han et al., 2003, Tsuruoka et al., 2003b). Since the LC neurons activated by noxious stimuli project to somatosensory thalamic nuclei, it is suggested that the ascending projections from the LC may also modulate nociceptive sensory processing within the thalamus (Voisin et al., 2005).
Coeruleospinal pain inhibitory system exhibits dynamic changes in response to nociceptive inputs following inflammation and peripheral nerve injury. Spinal antinociception induced by electrical stimulation of the LC was significantly weaker in nerve-injured than control animals (Viisanen and Pertovaara, 2007). In contrast to this finding, the LC has a strong spinal antinociceptive influence in animals with inflammation (Tsuruoka and Willis, 1996, Tsuruoka et al., 2003a).
Extracellular signal-regulated kinases (ERK1 and ERK2) are members of the serine/threonine protein kinases implicated in the transduction of neurotrophic and neurochemical signals from the cell surface to the nucleus (Grewal et al., 1999). ERK plays important roles in synaptic plasticity and memory formation (Sweatt, 2001), and phosphorylated ERK (p-ERK), an activated form of ERK, has been used as a marker of neural activation (Ji et al., 2002, Kawasaki et al., 2004, Shimizu et al., 2006).
Many reports have revealed that ERK activation in the spinal dorsal horn and primary sensory neurons contributes to nociception (Dai et al., 2002, Ji et al., 2002) and we have recently documented significant roles of ERK activation in the supraspinal structures including the RVM on nociceptive sensory processing. Activation of ERK in the RVM is involved in thermal hyperalgesia during peripheral inflammation (Imbe et al., 2005, Imbe et al., 2008). However, mechanisms underlying the dynamic changes in another main structure of descending pain modulatory system, the LC, remain unknown.
Several studies have demonstrated that ERK is also activated in the LC under several conditions including immobilization stress, opioid withdrawal, and anesthesia (Hebert et al., 2005, Kwon et al., 2006, Schulz and Hollt, 1998, Springell et al., 2005); however, no studies have assessed if noxious stimulation could induce ERK activation in the LC as was seen in the RVM.
In the present study, we examined the activation of ERK in the LC following injection of formalin or complete Freund's adjuvant (CFA) into the rat hindpaw in order to clarify changes of signal transduction system in the LC after acute noxious stimulation or chronic inflammation. The results show that formalin injection into the rat hindpaw significantly increases phospho-ERK-immunoreactive (p-ERK-IR) neurons in the LC.
Section snippets
Nocifensive behavior following injection of formalin or CFA into the hindpaw
Formalin injection induced the intense nocifensive behaviors, such as licking or biting of the injected paw, for the observation period. In contrast, CFA injection did not induce those behaviors except for the first 3-min interval after the injection (Fig. 1). The repeated ANOVA revealed a significant group difference between the formalin and CFA groups (P < 0.0001, Fig. 1).
Activation of ERK in the LC following injection of formalin or CFA into the hindpaw
A number of p-ERK-IR neurons were observed in the LC of rats with injections of formalin, CFA and saline or restraint (Fig. 2
Discussion
The present study clearly showed that acute noxious stimulation induced by formalin injection into the hindpaw resulted in a significant increase in p-ERK-IR in the LC for 1 h after the injection. We observed bilateral activation of ERK in the LC after unilateral formalin injection. Our finding is in accordance with the previous studies showing bilateral Fos expression in the LC after unilateral injection of carrageenan or formalin into the rat paw (Han et al., 2003, Tsuruoka et al., 2003b).
Animals
Male Sprague–Dawley rats (Japan SLC, Shizuoka, Japan) weighing 238–450 g were used in all experiments. The animals were housed two per cage, maintained under a 12-hour light–dark cycle, and allowed free access to food and water. The experiments were approved by the Animal Care Committee of Wakayama Medical University. All experiments conformed to the National Institutes of Health Guide for the Care and Use of the Laboratory Animals (NIH Publications No. 99-158 revised 2002). All efforts were
Acknowledgments
This study was supported in part by a Grant-in-Aid for Scientific Research (C) from Japan Society for the Promotion of Science (18613021).
References (43)
- et al.
Formalin- or adjuvant-induced peripheral inflammation increases neurokinin-1 receptor gene expression in the mouse
Brain Res.
(2003) - et al.
Increased transcription of the tyrosine hydroxylase gene in individual locus coeruleus neurons following footshock stress
Neuroscience
(2000) - et al.
Alpha2-adrenoceptor antagonists enhance responses of dorsal horn neurones to formalin induced inflammation
Eur. J. Pharmacol.
(1998) - et al.
Extracellular-signal-regulated kinase signalling in neurons
Curr. Opin. Neurobiol.
(1999) - et al.
Differential activation of spinal cord dynorphin and enkephalin neurons during hyperalgesia: evidence using cDNA hybridization
Brain Res.
(1988) - et al.
Effects of peripheral inflammation on activation of ERK in the rostral ventromedial medulla
Brain Res.
(2005) - et al.
Activation of ERK in the rostral ventromedial medulla is involved in hyperalgesia during peripheral inflammation
Brain Res.
(2008) - et al.
Central sensitization and LTP: do pain and memory share similar mechanisms?
Trends Neurosci.
(2003) - et al.
Activation of locus coeruleus by prefrontal cortex is mediated by excitatory amino acid inputs
Brain Res.
(1997) - et al.
The effect of single or repeated restraint stress on several signal molecules in paraventricular nucleus, arcuate nucleus and locus coeruleus
Neuroscience
(2006)
Formalin-induced nociception activates a monoaminergic descending inhibitory system
Brain Res.
An improved method for assessing mechanical allodynia in the rat
Physiol. Behav.
Stress-triggered activation of gene expression in catecholaminergic systems: dynamics of transcriptional events
Trends Neurosci.
Phosphorylation of extracellular signal-regulated kinase in medullary and upper cervical cord neurons following noxious tooth pulp stimulation
Brain Res.
Release of neurotransmitters in the locus coeruleus
Prog. Neurobiol.
Descending modulation from the region of the locus coeruleus on nociceptive sensitivity in a rat model of inflammatory hyperalgesia
Brain Res.
Coeruleospinal inhibition of nociceptive processing in the dorsal horn during unilateral hindpaw inflammation in the rat
Pain
Unilateral hindpaw inflammation induces bilateral activation of the locus coeruleus and the nucleus subcoeruleus in the rat
Brain Res. Bull.
Morphological substrates underlying opioid, epinephrine and gamma-aminobutyric acid inhibitory actions in the rat locus coeruleus
Brain Res. Bull.
Influence of peripheral nerve injury on response properties of locus coeruleus neurons and coeruleospinal antinociception in the rat
Neuroscience
The function of noradrenergic neurons in mediating antinociception induced by electrical stimulation of the locus coeruleus in two different sources of Sprague–Dawley rats
Brain Res.
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2016, NeuroscienceCitation Excerpt :Likewise, in the inflammatory pain model induced by unilateral hindpaw injection of carrageenan, bilateral expression of c-Fos protein was evident in the LC and SC region (Tsuruoka et al., 2003). The inflammation caused by formalin injection, or by that of complete Freund’s adjuvant (CFA) to induce monoarthritis, induces a bilateral and transient increase of pERK1/2 expression in the LC (Imbe et al., 2009). However, no differences in the expression of pERK1/2 were found in the LC either 4 or 14 days after CFA injection (Borges et al., 2014).
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2016, Brain Research BulletinCitation Excerpt :By dynamic cell count in this image analysis system, brightness range was set such that only specific pCREB-IR, ΔFosB-IR or acetylated histone H3-IR nuclei were accurately discriminated from the background in the outlined areas. Area’s boundaries were defined according to the cytoarchitectonic atlas (Paxinos and Watson, 1998) and the previous studies (Imbe et al., 2009, 2013). The number of positive cells in the outlined area was divided by the area of the outlined area (/mm2).
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2015, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :This result could be interpreted as an activation of the descending noradrenergic pathways. Conversely, this earlier activation of ERK1/2 observed in the LC in the CFA-induced model was no longer significantly observed when this condition was extended to more prolonged time-points (maximum of 7 h after induction) (Imbe et al., 2009). When considering prolonged painful states, a recent study from our group showed that the pERK1/2/tERK1/2 ratio in the LC was increased at 4, 14 and 28 days after CFA injection in the tibio-tarsal joint, being this increase particularly evident and significant at 28 days of disease (Borges et al., 2014).