T. Rouwette

The amygdala, a relay station for switching on and off pain

Neuropathic pain is strongly associated with mood disorders like anxiety and depression. Corticotropin‐releasing factor (CRF) plays a prominent role in these disorders as it is up‐regulated in limbic structures such as the amygdala, upon experimentally induced neuropathy. This review discusses recent literature on the role of CRF in pain processing and highlights the amygdala as a potential hot spot in supraspinal descending pain control. Many studies have demonstrated analgesic effects of CRF following local and systemic administration, but more recently also hyperalgesic effects were shown upon endogenous amygdalar CRF increase or by blocking the CRF type 1 receptor (CRFR1). On the basis of the reviewed literature, we postulate a central mechanism for pain control in which the amygdala plays a critical role by switching on and off chronic pain. In this mechanism, upon pain stimuli, CRFR1 in the amygdala is activated by CRF to induce hyperalgesia. When the activated CRFR1 is internalized (pain initiation), it triggers the translocation of the cytoplasmic CRF type 2 receptor (CRFR2) to the plasma membrane. Here, CRFR2 can be recruited by either high (pharmacological) concentrations of CRF or by endogenous CRFR2 ligands, the urocortins, leading to analgesia (pain termination). This on–off switching of pain is completed by redistribution of the CRF receptors to their initial activity state. We furthermore propose that in neuropathic pain, this mechanism is dysregulated and causes a state of permanent hyperalgesia, and present an integrative (patho)physiological model for the way disturbed CRF receptor signalling in the amygdala could initiate neuropathic pain.

The role of brain-derived neurotrophic factor in different animal models of neuropathic pain

Even in present day pain therapy, neuropathic pain remains a challenge for clinicians to treat and a challenge for researchers to investigate. Different animal models have been developed to mimic neuropathic pain. Neurotrophins such as nerve growth factor, brain‐derived neurotrophic factor and neurotrophin 3 have been studied extensively in these models, yet few review articles concerning brain‐derived neurotrophic factor have been published. This article reassesses the literature concerning brain‐derived neurotrophic factor expression in the sciatic nerve chronic constriction injury model, the sciatic nerve transection model, the spinal nerve ligation model and the spinal nerve transection model and discusses differences in regulation of brain‐derived neurotrophic factor between these models and their causality with neuropathic pain.

Differential responses of corticotropin-releasing factor and urocortin 1 to acute pain stress in the rat brain

It has been hypothesized that corticotropin-releasing factor (CRF) and its related neuropeptide urocortin 1 (Ucn1) play different roles in the initiation and adaptive phases of the stress response, which implies different temporal dynamics of these neuropeptides in response to stressors. We have tested the hypothesis that acute pain stress (APS) differentially changes the dynamics of CRF expression in the paraventricular nucleus of the hypothalamus (PVN), oval subdivision of the bed nucleus of the stria terminalis (BSTov) and central amygdala (CeA), and the dynamics of Ucn1 expression in the midbrain non-preganglionic Edinger-Westphal nucleus (npEW). Thirty minutes after APS, induced by a formalin injection into the left hind paw, PVN, BSTov, CeA and npEW all showed a peak in cFos mRNA expression that was followed by a robust increase in cFos protein-immunoreactivity, indicating a rapid increase in (immediate early) gene expression in all four brain nuclei. CRF-dynamics, however, were affected by APS in a brain nucleus-specific way: in the PVN, CRF-immunoreactivity was minimal at 60 min after APS and concomitant with a marked increase in plasma corticosterone, whereas in the BSTov not CRF peptide but CRF mRNA peaked at 60 min, and in the CeA a surge of CRF peptide occurred as late as 240 min. The npEW differed from the other centers, as Ucn1 mRNA and Ucn1 peptide peaked at 120 min. These results support our hypothesis that each of the four brain centers responds to APS with CRF/Ucn1 dynamics that are specific as to nature and timing. In particular, we propose that CRF in the PVN plays a major role in the initiation phase, whereas Ucn1 in the npEW may act in the later, termination phase of the adaptation response to APS.

Experimental neuropathy increases limbic forebrain CRF.

Neuropathic pain is often accompanied by stress, anxiety and depression. Although there is evidence for involvement of corticotropin‐releasing factor (CRF), the detailed neuronal basis of these pain‐related mood alterations is unknown. This study shows that peripheral mononeuropathy was accompanied by changes in limbic forebrain CRF, but did not lead to changes in the functioning of the hypothalamo‐pituitary–adrenal axis and the midbrain Edinger–Westphal centrally projecting (EWcp) neuron population, which play main roles in the organisms response to acute pain. Twenty‐four days after chronic constriction injury (CCI) of the rat sciatic nerve, the oval bed nucleus of the stria terminalis (BSTov) contained substantially more Crf mRNA as did the central amygdala (CeA), which, in addition, possessed more CRF. In contrast, Crf mRNA and CRF contents of the hypothalamic paraventricular nucleus (PVN) were unaffected by CCI. Similarly, EWcp neurons, producing the CRF family member urocortin 1 (Ucn1) and constitutively activated by various stressors including acute pain, did not show an effect of CCI on Ucn1 mRNA or Ucn1. Also, the immediate early gene products cFos and deltaFosB in the EWcp were unaffected by CCI. These results indicate that neuropathic pain does not act via the HPA‐axis or the EWcp, but includes a main role of Crf in the limbic system, which is in clear contrast to stressors like acute and chronic pain, which primarily act on the PVN and the EWcp.

Effects of chronic administration of amitriptyline, gabapentin and minocycline on spinal brain-derived neurotrophic factor expression and neuropathic pain behavior in a rat chronic constriction injury model

Background In animal models of neuropathic pain (NP), promising results have been reported with the administration of minocycline, possibly through inhibition of spinal brain-derived neurotrophic factor (BDNF) expression. No data are available on the effect of amitriptyline and gabapentin on spinal BDNF expression. If the mechanism of action of the latter drugs does not involve brain-derived NP inhibition, further clinical research in BDNF is warranted. Methods In this placebo-controlled study, we investigated the effects of amitriptyline (5 mg/kg), gabapentin (50 mg/kg), and minocycline (25 mg/kg) twice a day on NP behavior in a sciatic chronic constriction injury (CCI) rat model. Drug treatment started 7 days after CCI and lasted 14 days. At postoperative day 21, spinal BDNF expression in laminae I and II was quantified using immunocytochemistry. Results Sciatic CCI resulted in NP behavior throughout the duration of the experiment in the placebo group. When administered for 2 weeks, minocycline (P ⩽ 0.001) and amitriptyline (P ⩽ 0.05), but not gabapentin, reduced thermal hyperalgesia. None of these drugs reduced mechanical allodynia. As opposed to amitriptyline and gabapentin, 2 weeks of treatment with minocycline reduced brain-derived, neurotrophic factor immunoreactivity (P ⩽ 0.05) in the ipsilateral dorsal horn. Conclusions Minocycline and amitriptyline both reduce NP behavior in a sciatic CCI rat model, but only minocycline reduces spinal BDNF, indicating different modes of action of these 2 drugs. The observed actions of minocycline closely fit the clinical needs for the treatment of NP.

Acute pain increases phosphorylation of DCLK-long in the edinger-westphal nucleus but not in the hypothalamic paraventricular nucleus of the rat

UNLABELLED The doublecortin-like kinase (DCLK) gene is crucially involved in neuronal plasticity and microtubule-guided retrograde transport of signaling molecules. We have explored the possibility that DCLK is involved in pain-induced signaling events in adult male Wistar rats. Our results show that both DCLK-short and DCLK-long splice variants are present in the cell body and proximal dendrites of neurons in stress-related nuclei, ie, the paraventricular nucleus of the hypothalamus (PVN) and the non-preganglionic Edinger-Westphal nucleus (npEW) in the rostroventral periaqueductal grey. We found that DCLK-long but not DCLK-short is phosphorylated in its serine/proline-rich domain. Furthermore, we demonstrate that phosphorylation of DCLK-long in the npEW is increased by acute pain, whereas DCLK-long phosphorylation in the PVN remains unaffected. This is the first report revealing that DCLK isoforms in the PVN and npEW occur in the adult mammalian brain and that pain differentially affects DCLK-long-mediated neuronal plasticity in these 2 stress-sensitive brain centers. PERSPECTIVE Pain is a burden for society and the individual, and although the mechanisms underlying pain are relatively well known, its treatment remains difficult and incomplete. Pain stress can lead to diseases like chronic pain and depression. The differential DCLK-phosphorylation in stress-sensitive brain areas is a potential novel therapeutic target in pain research.

De amygdala, een schakelstation voor het aan- en uitzetten van pijn: de rol van limbisch corticotropin-releasing factor bij neuropathische pijn

Corticotropin-releasing factor (CRF) is essentieel bij stressadaptatie en veroorzaakt fysiologische stressresponsen via de hypothalamus-hypofyse-bijnier-as (HHB-as), wat leidt tot een verscheidenheid aan gedragsveranderingen en autonome en endocriene effecten om fysiologische en mentale homeostase te waarborgen (Chrousos & Gold, 1992; Smagin & Dunn, 2000; Vale et al., 1981). Dit gebeurt doordat CRF als neurotransmitter en/of neuromodulator op het centrale zenuwstelsel (CZS) werkt, met de limbische bed-nucleus van de stria terminalis (BST) en de centrale amygdala (CeA) (Deyama et al., 2007; Ji & Neugebauer, 2008) als belangrijke inputgebieden. Door chronische pijn wordt het functioneren van de HHB-as vaak ontregeld. Hierdoor kunnen angststoornissen en depressie optreden, ziekten die regelmatig geassocieerd blijken met een verstoorde werking van limbisch CRF (Arborelius et al., 1999; Blackburn-Munro & Blackburn-Munro, 2001). Recent is de sterke link tussen pijnverwerking en CRF beschreven (Lariviere & Melzack, 2000) en bewijs voor de betrokkenheid van limbisch CRF bij nociceptieve gevoeligheid, ofwel de gewaarwording van pijn, tijdens neuropathische pijn neemt toe (Bomholt et al., 2005; Rouwette et al., 2012a; Ulrich-Lai et al., 2006). Dit review geeft een overzicht van uitkomsten uit recent onderzoek naar hersengebieden die betrokken zijn bij het optreden van neuropathische pijn, waarbij de nadruk ligt op de rol hierbij van CRF. De amygdala, een kern in de temporaalkwab die lijkt te kunnen schakelen tussen nociceptie en analgesie, wordt beschouwd als belangrijk hersengebied voor pijnverwerking.AbstractCorticotropin-releasing factor (CRF) plays a prominent role in mood disorders like anxiety and depression. Upon experimentally-induced neuropathy, it is up-regulated in limbic structures such as the amygdala. This review discusses the literature on the role of CRF in pain processing and highlights the amygdala as key center in pain control. Not only has CRF analgesic effects following local and systemic administration, but more recently also hyperalgesic effects were shown upon endogenous amygdalar CRF increase or by blocking the CRF type 1 receptor (CRFR1). We here postulate a central mechanism for pain control with the amygdala as critical brain component in turning the sensation of pain on and off. Upon painful stimuli, CRFR1 in the amygdala is activated by CRF and induces hyperalgesia. The activated CRFR1 is then internalized (pain initiation) to trigger the translocation of the cytoplasmic CRFR2 to the plasma membrane. This CRFR2 can be recruited by either high (pharmacological) concentrations of CRF or by endogenous CRFR2 ligands, such as urocortins, which leads to analgesia (pain termination). Redistribution of the CRF receptors to their initial locations and activity states completes the on-off switching. We propose that in neuropathic pain, this mechanism is dysregulated, which leads to a state of permanent hyperalgesia, and we present an integrative (patho)physiological model for the way disturbed CRF receptor signaling in the amygdala could initiate neuropathic pain.