Abstract
Background
Chronic pain and stress-related psychopathologies, such as depression and anxiety-associated
abnormalities, are mutually reinforcing; however, the neuronal circuits and mechanisms
that underlie this reinforcement are still not well understood. Pituitary adenylate
cyclase-activating polypeptide (PACAP; Adcyap1) and its cognate PAC1 receptor (Adcyap1r1) are expressed in peripheral nociceptive pathways, participate in anxiety-related
responses and have been have been linked to posttraumatic stress disorder and other
mental health afflictions.
Methods
Using immunocytochemistry, pharmacological treatments and behavioral testing techniques,
we have used a rodent partial sciatic nerve chronic constriction injury model (n = 5–8 per group per experiment) to evaluate PACAP plasticity and signaling in nociceptive
and stress-related behaviors.
Results
We show that chronic neuropathic pain increases PACAP expression at multiple tiers
along the spinoparabrachioamygdaloid tract. Furthermore, chronic constriction injury
bilaterally augments nociceptive amygdala (in the central nucleus of the amygdala
[CeA]) PACAP immunoreactivity, extracellular signal–regulated kinase phosphorylation,
and c-Fos activation, in parallel with heightened anxiety-like behavior and nociceptive
hypersensitivity. Acute CeA infusions with the PACAP receptor antagonist PACAP(6-38)
blocked chronic constriction injury–induced behavioral responses. Additionally, pretreatments
with inhibitors of mitogen-activated protein kinase enzymes or endocytosis to block
endosomal PACAP receptor extracellular signal–regulated kinase signaling attenuated
PACAP-induced CeA neuronal activation and nociceptive responses.
Conclusions
Our data suggest that chronic pain-induced PACAP neuroplasticity and signaling in
spinoparabrachioamygdaloid projections have an impact on CeA stress- and nociception-associated
maladaptive responses, which can be ameliorated upon receptor antagonism even during
injury progression. Thus, the PACAP pathway provides for an important mechanism underlying
the intersection of stress and chronic pain pathways via the amygdala.
Keywords
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References
- Understanding the co-occurrence of anxiety disorders and chronic pain: State-of-the-art.Depress Anxiety. 2009; 26: 888-901
- The shared neuroanatomy and neurobiology of comorbid chronic pain and PTSD: Therapeutic implications.Clin J Pain. 2015; 31: 363-374
- The amygdala between sensation and affect: A role in pain.J Mol Psychiatry. 2013; 1: 9
- Involvement of the spino-parabrachio-amygdaloid and -hypothalamic pathways in the autonomic and affective emotional aspects of pain.Prog Brain Res. 1996; 107: 243-255
- Pain pathways and parabrachial circuits in the rat.Exp Physiol. 2002; 87: 251-258
- The amygdala, a relay station for switching on and off pain.Eur J Pain. 2012; 16: 782-792
- Neuronal circuitry for pain processing in the dorsal horn.Nat Rev Neurosci. 2010; 11: 823-836
- Synaptic plasticity in the amygdala in a model of arthritic pain: Differential roles of metabotropic glutamate receptors 1 and 5.J Neurosci. 2003; 23: 52-63
- Protein kinase A-dependent enhanced NMDA receptor function in pain-related synaptic plasticity in rat amygdala neurones.J Physiol. 2005; 564: 907-921
- Activation of the extracellular signal-regulated kinase in the amygdala modulates pain perception.J Neurosci. 2007; 27: 1543-1551
- Neurochemical properties of the synapses between the parabrachial nucleus-derived CGRP-positive axonal terminals and the GABAergic neurons in the lateral capsular division of central nucleus of amygdala.Mol Neurobiol. 2015; 51: 105-118
- Pain-related increase of excitatory transmission and decrease of inhibitory transmission in the central nucleus of the amygdala are mediated by mGluR1.Mol Pain. 2010; 6: 93
- Facilitation of synaptic transmission and pain responses by CGRP in the amygdala of normal rats.Mol Pain. 2010; 6: 10
- Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery.Pharmacol Rev. 2009; 61: 283-357
- Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor.Nature. 2011; 470: 492-497
- ADCYAP1R1 genotype associates with post-traumatic stress symptoms in highly traumatized African-American females.Am J Med Genet B Neuropsychiatr Genet. 2013; 162B: 262-272
- PAC1 receptor (ADCYAP1R1) genotype is associated with dark-enhanced startle in children.Mol Psychiatry. 2013; 18: 742-743
- Adcyap1r1 genotype, posttraumatic stress disorder, and depression among women exposed to childhood maltreatment.Depress Anxiety. 2013; 30: 251-258
- Neural mechanism of a sex-specific risk variant for posttraumatic stress disorder in the type I receptor of the pituitary adenylate cyclase activating polypeptide.Biol Psychiatry. 2015; 78: 840-847
- Altered psychomotor behaviors in mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP).Proc Natl Acad Sci U S A. 2001; 98: 13355-13360
- Noncompensation in peptide/receptor gene expression and distinct behavioral phenotypes in VIP- and PACAP-deficient mice.J Neurochem. 2006; 99: 499-513
- Comprehensive behavioral analysis of pituitary adenylate cyclase-activating polypeptide (PACAP) knockout mice.Front Behav Neurosci. 2012; 6: 58
- Altered emotional behavior in PACAP-type-I-receptor-deficient mice.Brain Res Mol Brain Res. 2001; 92: 78-84
- Stress hormone synthesis in mouse hypothalamus and adrenal gland triggered by restraint is dependent on pituitary adenylate cyclase-activating polypeptide signaling.Neuroscience. 2010; 165: 1025-1030
- PACAP centrally mediates emotional stress-induced corticosterone responses in mice.Stress. 2011; 14: 368-375
- Role of pituitary adenylate-cyclase activating polypeptide and Tac1 gene derived tachykinins in sensory, motor and vascular functions under normal and neuropathic conditions.Peptides. 2013; 43: 105-112
- Markedly reduced chronic nociceptive response in mice lacking the PAC1 receptor.Neuroreport. 2001; 12: 2215-2219
- Chronic stress increases pituitary adenylate cyclase-activating peptide (PACAP) and brain-derived neurotrophic factor (BDNF) mRNA expression in the bed nucleus of the stria terminalis (BNST): Roles for PACAP in anxiety-like behavior.Psychoneuroendocrinology. 2009; 34: 833-843
- PAC1 receptor antagonism in the bed nucleus of the stria terminalis (BNST) attenuates the endocrine and behavioral consequences of chronic stress.Psychoneuroendocrinology. 2014; 47: 151-165
- Regulation of bed nucleus of the stria terminalis PACAP expression by stress and corticosterone.J Mol Neurosci. 2014; 54: 477-484
- Parabrachial nucleus (PBn) pituitary adenylate cyclase activating polypeptide (PACAP) signaling in the amygdala: Implication for the sensory and behavioral effects of pain.Neuropharmacology. 2014; 86: 38-48
- Pituitary adenylate cyclase activating peptide expression in the rat dorsal root ganglia: Up-regulation after peripheral nerve injury.Neuroscience. 1996; 74: 1099-1110
- Changes in expression of PACAP in rat sensory neurons in response to sciatic nerve compression.Eur J Neurosci. 2004; 20: 1838-1848
- Hemispheric lateralization of a molecular signal for pain modulation in the amygdala.Mol Pain. 2008; 4: 24
- Hemispheric lateralization of pain processing by amygdala neurons.J Neurophysiol. 2009; 102: 2253-2264
- MAP kinase and pain.Brain Res Rev. 2009; 60: 135-148
- Role of extracellular signal-regulated kinase in synaptic transmission and plasticity of a nociceptive input on capsular central amygdaloid neurons in normal and acid-induced muscle pain mice.J Neurosci. 2011; 31: 2258-2270
- Importance of CRF receptor-mediated mechanisms of the bed nucleus of the stria terminalis in the processing of anxiety and pain.Neuropsychopharmacology. 2014; 39: 2633-2645
- Pituitary adenylyl cyclase-activating peptide stimulates extracellular signal-regulated kinase 1 or 2 (ERK1/2) activity in a Ras-independent, mitogen-activated protein kinase/ERK kinase 1 or -dependent manner in PC12 cells.J Biol Chem. 1997; 272: 19666-19671
- Stimulation of the ERK pathway by GTP-loaded Rap1 requires the concomitant activation of Ras, protein kinase C, and protein kinase A in neuronal cells.J Biol Chem. 2003; 278: 4778-4785
- Pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1HOP1 receptor activation coordinates multiple neurotrophic signaling pathways: Akt activation through phosphatidylinositol 3-kinase and vesicle endocytosis for neuronal survival.J Biol Chem. 2010; 285: 9749-9761
- PACAP-induced ERK activation in HEK cells expressing PAC1 receptors involves both receptor internalization and PKC signaling.Am J Physiol Cell Physiol. 2014; 306: C1068-C1079
- Regulation of GPCR signal networks via membrane trafficking.Mol Cell Endocrinol. 2011; 331: 205-214
- Beyond desensitization: Physiological relevance of arrestin-dependent signaling.Pharmacol Rev. 2010; 62: 305-330
- The effects of axotomy and preganglionic denervation on the expression of pituitary adenylate cyclase activating peptide (PACAP), galanin and PACAP type 1 receptors in the rat superior cervical ganglion.Brain Res. 1997; 775: 166-182
- Chronic pain leads to concomitant noradrenergic impairment and mood disorders.Biol Psychiatry. 2013; 73: 54-62
- Pituitary adenylate cyclase activating polypeptide in stress-related disorders: Data convergence from animal and human studies.Biol Psychiatry. 2014; 78: 167-177
- PACAP-deficient mice show attenuated corticosterone secretion and fail to develop depressive behavior during chronic social defeat stress.Psychoneuroendocrinology. 2013; 38: 702-715
- Critical role of calcitonin gene-related peptide 1 receptors in the amygdala in synaptic plasticity and pain behavior.J Neurosci. 2005; 25: 10717-10728
- Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior.J Neurosci. 2008; 28: 3861-3876
- Spinal CGRP1 receptors contribute to supraspinally organized pain behavior and pain-related sensitization of amygdala neurons.Pain. 2007; 132: 53-66
- Elucidating an affective pain circuit that creates a threat memory.Cell. 2015; 162: 363-374
- Pituitary adenylate cyclase-activating polypeptide induces postsynaptically expressed potentiation in the intra-amygdala circuit.J Neurosci. 2012; 32: 14165-14177
- Projections from the nociceptive area of the central nucleus of the amygdala to the forebrain: A PHA-L study in the rat.Eur J Neurosci. 2001; 14: 229-255
Article Info
Publication History
Published online: August 29, 2016
Accepted:
August 16,
2016
Received in revised form:
July 15,
2016
Received:
February 18,
2016
Identification
Copyright
© Society of Biological Psychiatry, 2016.
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- Extracellular Signal–Regulated Kinases: A Role for Mood Disorders and the Emotional Component of Pain?Biological PsychiatryVol. 81Issue 8
- PreviewMood disorders such as depression and anxiety disorders are frequent and disabling disorders with great socioeconomic impact. It is intriguing that there is a great degree of comorbidity of mood disorders with pain syndromes, which may be a consequence of a variety of disorders. Clinically, it is of note that a prevailing mood disorder can lead to a reinforcement of pain perception, whereas the experience of pain may cause or worsen mood disturbances. Such a vicious circle is a challenge for clinical management of comorbid patients but also for research dealing with its underlying pathophysiology.
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