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Intestinal inflammation and pain management
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ScienceDirect Intestinal inflammation and pain management Lilian Basso1,2,3, Arnaud Bourreille4,5 and Gilles Dietrich1,2,3 Intestinal inflammation results in the production of inflammatory pain-inducing mediators that may directly activate colon sensory neurons. Endogenous opioids produced by mucosal effector CD4+ T lymphocytes identified as colitogenic may paradoxically counterbalance the local proalgesic effect of inflammatory mediators by acting on opioid receptors expressed on sensory nerve endings. The review will focus on the endogenous immune-mediated regulation of visceral inflammatory pain, current pain treatments in inflammatory bowel diseases and prospectives on new opioid therapeutic opportunities to alleviate pain but avoiding common centrally-mediated side effects. Addresses 1 INSERM, U1043, Toulouse F-31300, France 2 CNRS, U5282, Toulouse F-31300, France 3 Universite´ de Toulouse, UPS, Toulouse F-31300, France 4 INSERM, U913, Nantes F-44093, France 5 Universite´ de Nantes, Institut des Maladies de l’Appareil Digestif, Nantes F-44093, France Corresponding author: Dietrich, Gilles ([email protected])
range of intracellular signaling pathways, resulting in channel sensitization and increased activity. Resident and/or infiltrating innate immune cells release inflammatory mediators including histamine, serotonin, or proteases which directly interact with their receptors on nociceptors and reduce the activation threshold of TRP channels. Most of endogenous agonists of TRP channels are bioactive lipids derived from arachidonic acid (AA) metabolism. The first lipid mediators described as TRPV1 agonists derive from the lipoxygenase (LOX) pathway such as 15-(S)-HPETE, 5-(S)-HETE and leukotriene B4 (LTB4). However, as exemplified with 5-(S)-HPETE or 15-(S)-HETE, LOX products are not all TRPV1 agonists [1]. Polyunsaturated fatty acid metabolites may also activate TRPV4. 5,6-epoxyeicosatrienoic acid (EET), an AA-derived metabolite originating from cytochrome epoxygenase (CYPe) pathway induces visceral hypersensitivity which is lost in TRPV4-deficient mice [2,3]. The pivotal role of 5,6EET in visceral pain has been recently strengthened in a study showing its significant increase in colon of patients with irritable bowel syndrome [3].
Current Opinion in Pharmacology 2015, 25:50–55 This review comes from a themed issue on Gastrointestinal Edited by Nathalie Vergnolle
http://dx.doi.org/10.1016/j.coph.2015.11.004
Stimulation of the channels/receptors depolarizes nociceptor terminals and generates action potential which results in neurotransmitter release at the pre-synaptic endings in the dorsal horn of the spinal cord. The nociceptive information is then conveyed to the brain through post-synaptic second-order neurons.
1471-4892/# 2015 Elsevier Ltd. All rights reserved.
Endogenous regulation of visceral inflammatory pain by opioid-producing mucosal CD4+ T lymphocytes Introduction Inflammation which occurs in response to tissue injuries involves a cascade of biochemical reactions resulting in the production of pain-inducing mediators. Normally innocuous stimuli become painful (allodynia) and painful sensations in response to noxious stimuli are increased (hyperalgesia). The painful message is conveyed from the periphery through nociceptors which include myelinated Ad fibers and unmyelinated C fibers. They are activated through a range of receptors/ion channels sensitive to heat, cold, protons, lipids, irritants and changes in osmolality or pressure. Transient receptor potential vanilloid (TRPV1 and TRPV4) and ankyrin (TRPA1), highly expressed on sensory neurons projecting from the colon, have been shown to play a central role in visceral inflammatory pain (Table 1). TRP channels are regulated by mechanisms involving a complex Current Opinion in Pharmacology 2015, 25:50–55
Crohn’s disease (CD) and ulcerative colitis (UC), the two main subtypes of inflammatory bowel disease (IBD), are chronic relapsing inflammatory disorders of the gastrointestinal tract. The commonly admitted IBD pathogenesis is a dysregulation of the immune response against commensal bacteria, which could be precipitated by an infection and a failure of the mucosal barrier function [4,5]. The inflammatory response induced by the entry of microbes into underlying tissues is sustained by an adaptive immune response which escapes endogenous regulation by regulatory T lymphocytes. The exacerbation of the immune response against luminal content is associated with the emergence of colitogenic Th1, Th17 or IL-17/ IFNg-producing CD4+ T lymphocytes and the development of colitis [6–8]. As it has been shown for NOD2 gene, some genetic polymorphisms conferring a functional deficiency of the intestinal barrier may also alter microbial clearance [9] or favor the commitment towards the inflammatory Th17 pathway [10]. www.sciencedirect.com
Intestinal inflammation and pain management Basso, Bourreille and Dietrich 51
Table 1 Inflammatory mediators triggering sensory neuron activation Receptors Ionic channels
TRPV1
Target cell
Heat pH Arachidonic acid metabolites (12-HPETE, 15-HPETE, 5-HETE, 15-HETE, 13-HODE, 9-HODE, LTB4) Anandamide N-arachidonoyl-dopamine N-oleoyl ethanolamine N-oleoyl dopamine Lysophosphatidic-acid
Sensory neurons Lymphocytes
Sensory neurons
TRPV4
pH ROS RNS Hydrogen sulfide 15d-PGJ2 Isoprostane (PGA1 and 8-isoPGA2, D12-PGJ2) Heat
Gut epithelial cells Glial Cells Immune cells
ASIC
Osmotic changes Shear stress Mechanical pressure Arachidonic acid metabolites (5,6-EET and 8,9-EET) pH
Voltage
Sensory neurons
TRPA1
Voltage gated sodium channels
Endogenous agonists
NaV 1.7 NaV 1.8 NaV 1.9
Sensory neurons
Sensory neurons
Inflammatory sensitizers (target receptor) Bradykinin (Bdkrb2) Histamine (H1R) NGF (TrkA)
IL1-b (IL1R1) IL6 (gp130) ATP (P2Y2) Substance P (NK1R) GDNF (GFRa) CCL3 (CCR1) CCL2 (CCR2) TNFa (TNFR1) Serine proteases (PAR2) Bradykinin (Bdkrb2)
Serine proteases (PAR2) PGE2 (PTGER2) IL17A (IL17RA) Histamin (H1R) Serotonin (5-HTR)
NGF (TrkA) Serotonin (5-HTR) IL1b (IL1R1) Bradykinin (Bdkrb2) PGE2 NGF (TrkA) IL1b (IL1R1) TNFa (TNFR1) CCL2 (CCR2)
Abbreviations: 12-HPETE, 12-hydroperoxyeicosatetraenoic acid; GDNF, glial cell line-derived neurotrophic factor; NGF, nerve growth factor; RNS, reactive nitrogen species; 15d-PGJ2, 15d-prostaglandin J2; PGE2, prostaglandin E2; Bdkrb2, B2 bradykinin receptor; TrkA, tropomyosin receptor kinase A; TRPV, transient receptor potential vanilloid; TRPA, transient receptor potential ankyrin; ASIC, acid sensing ion channels; GFRa, GDNF family receptor alpha; TNF, tumor necrosis factor; PAR, protease activated receptor; PTGER2, prostaglandin E receptor 2 (subtype EP2).
It is now well established that innate immune cells such as neutrophils, monocytes/macrophages or dendritic cells as well as adaptive immune cells such as CD4+ T lymphocytes produce opioids [11,12]. CD4+ T lymphocytes shown as the main source of endogenous opioids from hematopoietic origin are the most potent endogenous painkillers mobilized upon immune response to infection [11,13,14]. This opioid-dependent analgesic property is maintained in colitogenic effector CD4+ T lymphocytes including IFNg-producing Th1, IL-17-producing Th17 and IFNg/IL-17-producing T lymphocytes, thereby making colonic injuries painless [15,16]. As shown in the dextran sodium sulfate (DSS)-induced colitis model, the intensity of visceral inflammatory pain is inversely correlated with the density of effector T lymphocytes within the inflamed mucosa [15]. Alteration of the intestinal barrier induced by DSS promotes translocation www.sciencedirect.com
of bacteria from the lumen towards mucosa. Within the five first days of DSS treatment, activation of innate immune cells by bacteria or their products results in intestinal inflammation and visceral pain. The adaptive immune response against bacteria-derived antigens, which is initiated at the beginning of the bacterial invasion, results, a few days later, in the accumulation of effector opioid-producing CD4+ T lymphocytes [15]. These lymphocytes, which produce opioids independently on their Th1 or Th17 phenotype, release their opioid content after a new stimulation by the antigen in situ (Figure 1) [15,17]. The accumulation of opioidproducing T lymphocytes within the inflamed mucosa occurs in a period of time compatible with the inflammation-induced increase in opioid receptors on nerve endings [18–20] and leads to the relief of abdominal pain raised in the early phase of the colitis. The increased Current Opinion in Pharmacology 2015, 25:50–55
52 Gastrointestinal
Figure 1
bacteria
lumen
mucosa
1
Inflammatory mediators
innate immune cells
2 lymphatic vessel
and prolonged inflammation in asymptomatic or minimally symptomatic patients, a follow-up based on a combination of clinical, biological, endoscopic and radiological features is now highly recommended [27]. A treatment may be optimized even in an asymptomatic patient when the risk of intestinal damage is judged inacceptable by the physician.
dendritic cells
sensory neurons
4 blood vessel
CD4+ T lymphocytes
3 draining mesenteric lymph node Current Opinion in Pharmacology
Endogenous regulation of visceral inflammatory pain by mucosal CD4+ T lymphocytes. (1) The increase in intestinal permeability promotes bacterial translocation from lumen towards mucosa. Activation of epithelial and innate immune cells by bacteria-derived products triggers the release of inflammatory mediators inducing pain by stimulating sensory neurons. (2) Immature dendritic cells capture bacteria-derived antigens, mature and then migrate into draining lymph nodes. (3) Recognition of the bacteria-derived antigens by CD4+ T cells up-regulates opioid synthesis. (4) Effector CD4+ T cells migrate into inflammatory site close to sensory neurons and release their opioid content after a new stimulation by the cognate antigen in situ. Activation of opioid receptors on sensory nerve endings inhibits pain.
production of opioids, that has also been reported in patients with Crohn’s disease and ulcerative colitis [21], reduces the excitability of colonic sensory neurons [22,23].
Current pain treatment in IBD Ulcerative colitis (UC) and Crohn’s disease (CD) share similar characteristics but differ in term of location and symptoms. CD can affect every part of the digestive tract with a more frequent location in the terminal ileum and the ascending colon. UC is characterized by an inflammation limited to the colon and the rectum. Clinical indices of the disease activity developed to quantify the severity of the flares poorly correlate with the severity of mucosal damage in the digestive tract, as assessed by endoscopy or inflammatory biomarkers [24]. Accordingly, many clinical trials aiming to evaluate the efficacy of biotherapy in patients with CD show a discrepancy between clinical disease remission including pain and mucosal healing [25,26]. Taking into consideration that irreversible intestinal damage originates from a persistent Current Opinion in Pharmacology 2015, 25:50–55
Clinically, patients with CD often complain of abdominal pain or discomfort. The challenge for the physician is to discriminate abdominal pain resulting from acute or chronic complications of the disease from an irritable bowel syndrome (IBS) frequently associated with IBD. Usually, abdominal pain triggered by the meals may originate from a stricture. In this case, anti-spasmodic and other analgesics are often inefficient since the symptoms are due to the distension of the overlying noninflamed intestine or to the bacterial overgrowth. Steroids, biological or immunosuppressive therapies may be efficient depending on fibrosis extend. In case of failure, endoscopic dilatation or surgical resection are the only ways to treat efficiently the patient before the occurrence of complete intestinal obstruction. Acute abdominal pain may also result from perforation or abscess. In these cases, pain is recognized by the patient as unusual and is frequently associated with other signs such as fever and signs of peritoneal irritation. Although the global management of the disease includes pain treatment by intravenous level I or II analgesics, the objective remains the treatment of the disease itself. Chronic pain may persist in as many as 20% of patients with CD in clinical and biological remission [28]. The frequency of IBS-like symptoms in patients with IBD is 2–3 higher than in the general population and, up to 60% of the patients with CD reports symptoms of IBS including abdominal pain [29]. The occurrence of IBS-like symptoms in patients with IBD is significantly associated with an increase in the use of narcotics [30]. As a matter of fact, the use of opioids in IBD population is steadily increasing despite severe deleterious side effects including narcotic bowel syndrome [31]. In addition to wellknown side effects such as nausea, respiratory depression, sedation, gastro-oesophageal reflux or constipation, narcotics are also associated with an increased risk of severe infections and mortality in CD patients [32]. The increased bacterial translocation from the lumen to mucosa favored by the reduction of intestinal motility [33], together with the down-modulation of the immune response of the host has been proposed as a mechanism to explain the high incidence of infection in IBD patients treated with opiates.
New strategies in opioid therapy for intestinal inflammation The complex interplay between mediators leading to abdominal pain as well as the IBD and IBS symptoms www.sciencedirect.com
Intestinal inflammation and pain management Basso, Bourreille and Dietrich 53
overlaps make pain management difficult. Although opioids are not commonly approved for non-cancer chronic visceral pain treatment, their analgesic and anti-inflammatory properties in intestinal inflammation are sufficiently promising to search new strategies to reduce their side effects. It is now well admitted that the activation of peripheral opioid receptors is responsible for a large part of the analgesic effects induced by systemically injected opioid drugs [34,35,36,37,38,39,40,41–43]. The analgesic effects of intravenously administered DOR or MOR agonists are significantly reduced in conditional knock-out mice in which respective DOR or MOR receptors are deleted on Nav1.8+-expressing nociceptors [35,40]. To avoid or at least to minimize centrally mediated side effects of opioids, a number of new therapeutic strategies aim at restricting their action on opioid receptors expressed in periphery. Schematically, these strategies can be divided into those aiming to develop new processes or formulation to avoid the passage of opioid drugs across the blood brain barrier and those aiming to improve local endogenous opioid-mediated regulation of inflammation and pain. These latter strategies might have some advantages such as a weak desensitization and/or down-modulation of opioid receptors and thereby, a reduced tolerance [44–46].
Opioid agonists with peripheral activity The pivotal role of peripheral opioid receptors in the analgesic effects of opioid drugs has led to the development of new opioid ligands exhibiting a reduced capability to cross the blood–brain barrier. Because of their hydrophobicity, opiates easily penetrate the central nervous system by passive diffusion. To counteract their ability to cross the blood–brain barrier, the common procedure consists in increasing their hydrophilic properties. However, other chemical modifications such as glucuronidation may be used to reduce or slow down passage across the blood–brain barrier [47]. Development of new opioid-based anti-nociceptive drugs such as biphalin, a synthetic dimer of enkephalin-derived tetrapeptides with low side effects, has also been proposed as an alternative strategy [48]. The activation of opioid receptors restricted to the periphery might also be achieved with agonistic antibodies [49–52], whose molecular weight does not allow blood–brain barrier crossing. In the context of chronic pain management, the long half-life of antibodies (5–8 days for IgA or IgM to 3 weeks for IgG) may be advantageous. However, the use of antibodies from other species than human requires biochemical modifications, so-called humanization, to prevent immunization against therapeutic antibodies. Moreover, compared with opiate treatment, the cost-effectiveness of antibody therapies is higher. A new concept based on nanotechnologies has been recently proposed to mimic opioid-producing cells. www.sciencedirect.com
The strategy lies on the synthesis of liposomes encapsulating opioid drugs which specifically target the inflammatory site. To drive liposomes to the inflammatory site, antibodies targeting adhesion molecules typically upregulated on inflamed endothelial cells (e.g. ICAM-1) are inserted into the lipid bilayer of the particle. The pilot study shows that the delivery of opioid drugs by nanoparticles at the site of inflammation reduces both inflammation and related pain [53]. Compared to peripherally acting opioids, this strategy might be particularly relevant to relieve pain originating from inflammatory foci dispersed all along intestine.
Improvement of local endogenous opioid tone The amounts of opioids released by inflammatory cells entering the site of inflammation within few hours following tissue damage are not sufficient to spontaneously relieve inflammatory pain. However, inflammatory pain may be alleviated by locally injecting exogenous inflammatory mediators such as pro-inflammatory cytokines (IL-1b) or chemokines (CXCL2, CXCL8) [54]. Clinical observations suggest that the intensity of abdominal pain is rather dependent on the type of immune cells at the site of inflammation than the level of inflammation-induced tissue damage by itself. The intensity of visceral inflammatory pain is higher in an environment in which innate immune cells are dominant than in an environment enriched in T lymphocytes [15,16,22]. Thus, triggering the release of endogenous opioids from innate inflammatory cells and improving the migration of effector T lymphocytes into an inflammatory site appear as two complementary therapeutic options. Inflammation is associated with a huge production of proteases including the aminopeptidase N (APN) and neutral endopeptidase (NEP), two peptidases which shorten the half-life of opioid peptides. In order to enhance endogenous control of inflammatory pain by opioids locally produced by immune cells, inhibitors of peptidase activity have been developed. In rats, administration of peptidase inhibitors alleviates from inflammatory pain induced by injecting formalin [55] or complete Freund’s adjuvant [56] into hind paw. Treatment with peptidase inhibitors does not seem to be associated with classical opioid side-effects such as dependence [45] or alteration of locomotor activity and long-term memory [57].
Conclusion The risks related to the chronic use of opioids in intestinal inflammation often overload their beneficial effects. Most of the opioid side effects including nausea, vomiting but also constipation or reduced gastrointestinal motility [58] are at least in part dependent on stimulation of receptors within central nervous system. Given that endogenous opioids produced by intestinal effector CD4+ T lymphocytes as well as exogenous opioid drugs locally applied Current Opinion in Pharmacology 2015, 25:50–55
54 Gastrointestinal
display potent anti-nociceptive and anti-inflammatory properties [59], it can be assumed that an opioid supply restricted to periphery could be instrumental in preventing or reducing IBD flare-ups.
Conflicts of interest Nothing declared.
Acknowledgements This work is supported by the Institut National de la Sante´ et de la Recherche Me´dicale (INSERM), the Universite´ Paul Sabatier, Toulouse III, and the French Agence Nationale de la Recherche grant LYMPHOPIOID.
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44. Stein C, Pflu¨ger M, Yassouridis A, Hoelzl J, Lehrberger K, Welte C, Hassan AHS: No tolerance to peripheral morphine analgesia in presence of opioid expression in inflamed synovia. J Clin Invest 1996, 98:793-799. 45. Rougeot C, Robert F, Menz L, Bisson JF, Messaoudi M: Systemically active human opiorphin is a potent yet nonaddictive analgesic without drug tolerance effects. J Physiol Pharmacol 2010, 61:483-490. 46. Popik P, Kamysz E, Kreczko J, Wrobel M: Human opiorphin: the lack of physiological dependence, tolerance to antinociceptive effects and abuse liability in laboratory mice. Behav Brain Res 2010, 213:88-93. 47. Binning AR, Przesmycki K, Sowinski P, Morrison LM, Smith TW, Marcus P, Lees JP, Dahan A: A randomised controlled trial on the efficacy and side-effect profile (nausea/vomiting/ sedation) of morphine-6-glucuronide versus morphine for post-operative pain relief after major abdominal surgery. Eur J Pain 2011, 15:402-408. 48. Sobczak M, Pilarczyk A, Jonakowski M, Jarmuz A, Salaga M, Lipkowski AW, Fichna J: Anti-inflammatory and antinociceptive action of the dimeric enkephalin peptide biphalin in the mouse model of colitis: new potential treatment of abdominal pain associated with inflammatory bowel diseases. Peptides 2014, 60:102-106. 49. Mace G, Blanpied C, Emorine LJ, Druet P, Dietrich G: Morphinelike activity of natural human IgG autoantibodies is because of binding to the first and third extracellular loops of the muopioid receptor. J Biol Chem 1999, 274:20079-20082. 50. Mace G, Blanpied C, Emorine LJ, Druet P, Dietrich G: Isolation and characterization of natural human IgG with a morphinelike activity. Eur J Immunol 1999, 29:997-1003. 51. Mace G, Jaume M, Blanpied C, Stephan L, Coudert JD, Druet P, Dietrich G: Anti-mu-opioid-receptor IgG antibodies are commonly present in serum from healthy blood donors: evidence for a role in apoptotic immune cell death. Blood 2002, 100:3261-3268. 52. Ranganathan P, Chen H, Adelman MK, Schluter SF: Autoantibodies to the delta-opioid receptor function as opioid agonists and display immunomodulatory activity. J Neuroimmunol 2009, 217:65-73. 53. Hua S, Cabot PJ: Targeted nanoparticles that mimic immune cells in pain control inducing analgesic and anti-inflammatory actions: a potential novel treatment of acute and chronic pain condition. Pain Physician 2013, 16:E199-E216. 54. Rittner HL, Labuz D, Schaefer M, Mousa SA, Schulz S, Schafer M, Stein C, Brack A: Pain control by CXCR2 ligands through Ca2+regulated release of opioid peptides from polymorphonuclear cells. Faseb J 2006, 20:2627-2629. 55. Wisner A, Dufour E, Messaoudi M, Nejdi A, Marcel A, Ungeheuer MN, Rougeot C: Human opiorphin, a natural antinociceptive modulator of opioid-dependent pathways. Proc Natl Acad Sci U S A 2006, 103:17979-17984. 56. Schreiter A, Gore C, Labuz D, Fournie-Zaluski MC, Roques BP, Stein C, Machelska H: Pain inhibition by blocking leukocytic and neuronal opioid peptidases in peripheral inflamed tissue. Faseb J 2012, 26:5161-5171. 57. Javelot H, Messaoudi M, Garnier S, Rougeot C: Human opiorphin is a naturally occurring antidepressant acting selectively on enkephalin-dependent delta-opioid pathways. J Physiol Pharmacol 2010, 61:355-362. 58. Mori T, Shibasaki Y, Matsumoto K, Shibasaki M, Hasegawa M, Wang E, Masukawa D, Yoshizawa K, Horie S, Suzuki T: Mechanisms that underlie mu-opioid receptor agonistinduced constipation: differential involvement of mu-opioid receptor sites and responsible regions. J Pharmacol Exp Ther 2013, 347:91-99. 59. Philippe D, Dubuquoy L, Groux H, Brun V, Chuoi-Mariot MT, Gaveriaux-Ruff C, Colombel JF, Kieffer BL, Desreumaux P: Antiinflammatory properties of the mu-opioid receptor support its use in the treatment of colon inflammation. J Clin Invest 2003, 111:1329-1338. Current Opinion in Pharmacology 2015, 25:50–55
ScienceDirect Intestinal inflammation and pain management Lilian Basso1,2,3, Arnaud Bourreille4,5 and Gilles Dietrich1,2,3 Intestinal inflammation results in the production of inflammatory pain-inducing mediators that may directly activate colon sensory neurons. Endogenous opioids produced by mucosal effector CD4+ T lymphocytes identified as colitogenic may paradoxically counterbalance the local proalgesic effect of inflammatory mediators by acting on opioid receptors expressed on sensory nerve endings. The review will focus on the endogenous immune-mediated regulation of visceral inflammatory pain, current pain treatments in inflammatory bowel diseases and prospectives on new opioid therapeutic opportunities to alleviate pain but avoiding common centrally-mediated side effects. Addresses 1 INSERM, U1043, Toulouse F-31300, France 2 CNRS, U5282, Toulouse F-31300, France 3 Universite´ de Toulouse, UPS, Toulouse F-31300, France 4 INSERM, U913, Nantes F-44093, France 5 Universite´ de Nantes, Institut des Maladies de l’Appareil Digestif, Nantes F-44093, France Corresponding author: Dietrich, Gilles ([email protected])
range of intracellular signaling pathways, resulting in channel sensitization and increased activity. Resident and/or infiltrating innate immune cells release inflammatory mediators including histamine, serotonin, or proteases which directly interact with their receptors on nociceptors and reduce the activation threshold of TRP channels. Most of endogenous agonists of TRP channels are bioactive lipids derived from arachidonic acid (AA) metabolism. The first lipid mediators described as TRPV1 agonists derive from the lipoxygenase (LOX) pathway such as 15-(S)-HPETE, 5-(S)-HETE and leukotriene B4 (LTB4). However, as exemplified with 5-(S)-HPETE or 15-(S)-HETE, LOX products are not all TRPV1 agonists [1]. Polyunsaturated fatty acid metabolites may also activate TRPV4. 5,6-epoxyeicosatrienoic acid (EET), an AA-derived metabolite originating from cytochrome epoxygenase (CYPe) pathway induces visceral hypersensitivity which is lost in TRPV4-deficient mice [2,3]. The pivotal role of 5,6EET in visceral pain has been recently strengthened in a study showing its significant increase in colon of patients with irritable bowel syndrome [3].
Current Opinion in Pharmacology 2015, 25:50–55 This review comes from a themed issue on Gastrointestinal Edited by Nathalie Vergnolle
http://dx.doi.org/10.1016/j.coph.2015.11.004
Stimulation of the channels/receptors depolarizes nociceptor terminals and generates action potential which results in neurotransmitter release at the pre-synaptic endings in the dorsal horn of the spinal cord. The nociceptive information is then conveyed to the brain through post-synaptic second-order neurons.
1471-4892/# 2015 Elsevier Ltd. All rights reserved.
Endogenous regulation of visceral inflammatory pain by opioid-producing mucosal CD4+ T lymphocytes Introduction Inflammation which occurs in response to tissue injuries involves a cascade of biochemical reactions resulting in the production of pain-inducing mediators. Normally innocuous stimuli become painful (allodynia) and painful sensations in response to noxious stimuli are increased (hyperalgesia). The painful message is conveyed from the periphery through nociceptors which include myelinated Ad fibers and unmyelinated C fibers. They are activated through a range of receptors/ion channels sensitive to heat, cold, protons, lipids, irritants and changes in osmolality or pressure. Transient receptor potential vanilloid (TRPV1 and TRPV4) and ankyrin (TRPA1), highly expressed on sensory neurons projecting from the colon, have been shown to play a central role in visceral inflammatory pain (Table 1). TRP channels are regulated by mechanisms involving a complex Current Opinion in Pharmacology 2015, 25:50–55
Crohn’s disease (CD) and ulcerative colitis (UC), the two main subtypes of inflammatory bowel disease (IBD), are chronic relapsing inflammatory disorders of the gastrointestinal tract. The commonly admitted IBD pathogenesis is a dysregulation of the immune response against commensal bacteria, which could be precipitated by an infection and a failure of the mucosal barrier function [4,5]. The inflammatory response induced by the entry of microbes into underlying tissues is sustained by an adaptive immune response which escapes endogenous regulation by regulatory T lymphocytes. The exacerbation of the immune response against luminal content is associated with the emergence of colitogenic Th1, Th17 or IL-17/ IFNg-producing CD4+ T lymphocytes and the development of colitis [6–8]. As it has been shown for NOD2 gene, some genetic polymorphisms conferring a functional deficiency of the intestinal barrier may also alter microbial clearance [9] or favor the commitment towards the inflammatory Th17 pathway [10]. www.sciencedirect.com
Intestinal inflammation and pain management Basso, Bourreille and Dietrich 51
Table 1 Inflammatory mediators triggering sensory neuron activation Receptors Ionic channels
TRPV1
Target cell
Heat pH Arachidonic acid metabolites (12-HPETE, 15-HPETE, 5-HETE, 15-HETE, 13-HODE, 9-HODE, LTB4) Anandamide N-arachidonoyl-dopamine N-oleoyl ethanolamine N-oleoyl dopamine Lysophosphatidic-acid
Sensory neurons Lymphocytes
Sensory neurons
TRPV4
pH ROS RNS Hydrogen sulfide 15d-PGJ2 Isoprostane (PGA1 and 8-isoPGA2, D12-PGJ2) Heat
Gut epithelial cells Glial Cells Immune cells
ASIC
Osmotic changes Shear stress Mechanical pressure Arachidonic acid metabolites (5,6-EET and 8,9-EET) pH
Voltage
Sensory neurons
TRPA1
Voltage gated sodium channels
Endogenous agonists
NaV 1.7 NaV 1.8 NaV 1.9
Sensory neurons
Sensory neurons
Inflammatory sensitizers (target receptor) Bradykinin (Bdkrb2) Histamine (H1R) NGF (TrkA)
IL1-b (IL1R1) IL6 (gp130) ATP (P2Y2) Substance P (NK1R) GDNF (GFRa) CCL3 (CCR1) CCL2 (CCR2) TNFa (TNFR1) Serine proteases (PAR2) Bradykinin (Bdkrb2)
Serine proteases (PAR2) PGE2 (PTGER2) IL17A (IL17RA) Histamin (H1R) Serotonin (5-HTR)
NGF (TrkA) Serotonin (5-HTR) IL1b (IL1R1) Bradykinin (Bdkrb2) PGE2 NGF (TrkA) IL1b (IL1R1) TNFa (TNFR1) CCL2 (CCR2)
Abbreviations: 12-HPETE, 12-hydroperoxyeicosatetraenoic acid; GDNF, glial cell line-derived neurotrophic factor; NGF, nerve growth factor; RNS, reactive nitrogen species; 15d-PGJ2, 15d-prostaglandin J2; PGE2, prostaglandin E2; Bdkrb2, B2 bradykinin receptor; TrkA, tropomyosin receptor kinase A; TRPV, transient receptor potential vanilloid; TRPA, transient receptor potential ankyrin; ASIC, acid sensing ion channels; GFRa, GDNF family receptor alpha; TNF, tumor necrosis factor; PAR, protease activated receptor; PTGER2, prostaglandin E receptor 2 (subtype EP2).
It is now well established that innate immune cells such as neutrophils, monocytes/macrophages or dendritic cells as well as adaptive immune cells such as CD4+ T lymphocytes produce opioids [11,12]. CD4+ T lymphocytes shown as the main source of endogenous opioids from hematopoietic origin are the most potent endogenous painkillers mobilized upon immune response to infection [11,13,14]. This opioid-dependent analgesic property is maintained in colitogenic effector CD4+ T lymphocytes including IFNg-producing Th1, IL-17-producing Th17 and IFNg/IL-17-producing T lymphocytes, thereby making colonic injuries painless [15,16]. As shown in the dextran sodium sulfate (DSS)-induced colitis model, the intensity of visceral inflammatory pain is inversely correlated with the density of effector T lymphocytes within the inflamed mucosa [15]. Alteration of the intestinal barrier induced by DSS promotes translocation www.sciencedirect.com
of bacteria from the lumen towards mucosa. Within the five first days of DSS treatment, activation of innate immune cells by bacteria or their products results in intestinal inflammation and visceral pain. The adaptive immune response against bacteria-derived antigens, which is initiated at the beginning of the bacterial invasion, results, a few days later, in the accumulation of effector opioid-producing CD4+ T lymphocytes [15]. These lymphocytes, which produce opioids independently on their Th1 or Th17 phenotype, release their opioid content after a new stimulation by the antigen in situ (Figure 1) [15,17]. The accumulation of opioidproducing T lymphocytes within the inflamed mucosa occurs in a period of time compatible with the inflammation-induced increase in opioid receptors on nerve endings [18–20] and leads to the relief of abdominal pain raised in the early phase of the colitis. The increased Current Opinion in Pharmacology 2015, 25:50–55
52 Gastrointestinal
Figure 1
bacteria
lumen
mucosa
1
Inflammatory mediators
innate immune cells
2 lymphatic vessel
and prolonged inflammation in asymptomatic or minimally symptomatic patients, a follow-up based on a combination of clinical, biological, endoscopic and radiological features is now highly recommended [27]. A treatment may be optimized even in an asymptomatic patient when the risk of intestinal damage is judged inacceptable by the physician.
dendritic cells
sensory neurons
4 blood vessel
CD4+ T lymphocytes
3 draining mesenteric lymph node Current Opinion in Pharmacology
Endogenous regulation of visceral inflammatory pain by mucosal CD4+ T lymphocytes. (1) The increase in intestinal permeability promotes bacterial translocation from lumen towards mucosa. Activation of epithelial and innate immune cells by bacteria-derived products triggers the release of inflammatory mediators inducing pain by stimulating sensory neurons. (2) Immature dendritic cells capture bacteria-derived antigens, mature and then migrate into draining lymph nodes. (3) Recognition of the bacteria-derived antigens by CD4+ T cells up-regulates opioid synthesis. (4) Effector CD4+ T cells migrate into inflammatory site close to sensory neurons and release their opioid content after a new stimulation by the cognate antigen in situ. Activation of opioid receptors on sensory nerve endings inhibits pain.
production of opioids, that has also been reported in patients with Crohn’s disease and ulcerative colitis [21], reduces the excitability of colonic sensory neurons [22,23].
Current pain treatment in IBD Ulcerative colitis (UC) and Crohn’s disease (CD) share similar characteristics but differ in term of location and symptoms. CD can affect every part of the digestive tract with a more frequent location in the terminal ileum and the ascending colon. UC is characterized by an inflammation limited to the colon and the rectum. Clinical indices of the disease activity developed to quantify the severity of the flares poorly correlate with the severity of mucosal damage in the digestive tract, as assessed by endoscopy or inflammatory biomarkers [24]. Accordingly, many clinical trials aiming to evaluate the efficacy of biotherapy in patients with CD show a discrepancy between clinical disease remission including pain and mucosal healing [25,26]. Taking into consideration that irreversible intestinal damage originates from a persistent Current Opinion in Pharmacology 2015, 25:50–55
Clinically, patients with CD often complain of abdominal pain or discomfort. The challenge for the physician is to discriminate abdominal pain resulting from acute or chronic complications of the disease from an irritable bowel syndrome (IBS) frequently associated with IBD. Usually, abdominal pain triggered by the meals may originate from a stricture. In this case, anti-spasmodic and other analgesics are often inefficient since the symptoms are due to the distension of the overlying noninflamed intestine or to the bacterial overgrowth. Steroids, biological or immunosuppressive therapies may be efficient depending on fibrosis extend. In case of failure, endoscopic dilatation or surgical resection are the only ways to treat efficiently the patient before the occurrence of complete intestinal obstruction. Acute abdominal pain may also result from perforation or abscess. In these cases, pain is recognized by the patient as unusual and is frequently associated with other signs such as fever and signs of peritoneal irritation. Although the global management of the disease includes pain treatment by intravenous level I or II analgesics, the objective remains the treatment of the disease itself. Chronic pain may persist in as many as 20% of patients with CD in clinical and biological remission [28]. The frequency of IBS-like symptoms in patients with IBD is 2–3 higher than in the general population and, up to 60% of the patients with CD reports symptoms of IBS including abdominal pain [29]. The occurrence of IBS-like symptoms in patients with IBD is significantly associated with an increase in the use of narcotics [30]. As a matter of fact, the use of opioids in IBD population is steadily increasing despite severe deleterious side effects including narcotic bowel syndrome [31]. In addition to wellknown side effects such as nausea, respiratory depression, sedation, gastro-oesophageal reflux or constipation, narcotics are also associated with an increased risk of severe infections and mortality in CD patients [32]. The increased bacterial translocation from the lumen to mucosa favored by the reduction of intestinal motility [33], together with the down-modulation of the immune response of the host has been proposed as a mechanism to explain the high incidence of infection in IBD patients treated with opiates.
New strategies in opioid therapy for intestinal inflammation The complex interplay between mediators leading to abdominal pain as well as the IBD and IBS symptoms www.sciencedirect.com
Intestinal inflammation and pain management Basso, Bourreille and Dietrich 53
overlaps make pain management difficult. Although opioids are not commonly approved for non-cancer chronic visceral pain treatment, their analgesic and anti-inflammatory properties in intestinal inflammation are sufficiently promising to search new strategies to reduce their side effects. It is now well admitted that the activation of peripheral opioid receptors is responsible for a large part of the analgesic effects induced by systemically injected opioid drugs [34,35,36,37,38,39,40,41–43]. The analgesic effects of intravenously administered DOR or MOR agonists are significantly reduced in conditional knock-out mice in which respective DOR or MOR receptors are deleted on Nav1.8+-expressing nociceptors [35,40]. To avoid or at least to minimize centrally mediated side effects of opioids, a number of new therapeutic strategies aim at restricting their action on opioid receptors expressed in periphery. Schematically, these strategies can be divided into those aiming to develop new processes or formulation to avoid the passage of opioid drugs across the blood brain barrier and those aiming to improve local endogenous opioid-mediated regulation of inflammation and pain. These latter strategies might have some advantages such as a weak desensitization and/or down-modulation of opioid receptors and thereby, a reduced tolerance [44–46].
Opioid agonists with peripheral activity The pivotal role of peripheral opioid receptors in the analgesic effects of opioid drugs has led to the development of new opioid ligands exhibiting a reduced capability to cross the blood–brain barrier. Because of their hydrophobicity, opiates easily penetrate the central nervous system by passive diffusion. To counteract their ability to cross the blood–brain barrier, the common procedure consists in increasing their hydrophilic properties. However, other chemical modifications such as glucuronidation may be used to reduce or slow down passage across the blood–brain barrier [47]. Development of new opioid-based anti-nociceptive drugs such as biphalin, a synthetic dimer of enkephalin-derived tetrapeptides with low side effects, has also been proposed as an alternative strategy [48]. The activation of opioid receptors restricted to the periphery might also be achieved with agonistic antibodies [49–52], whose molecular weight does not allow blood–brain barrier crossing. In the context of chronic pain management, the long half-life of antibodies (5–8 days for IgA or IgM to 3 weeks for IgG) may be advantageous. However, the use of antibodies from other species than human requires biochemical modifications, so-called humanization, to prevent immunization against therapeutic antibodies. Moreover, compared with opiate treatment, the cost-effectiveness of antibody therapies is higher. A new concept based on nanotechnologies has been recently proposed to mimic opioid-producing cells. www.sciencedirect.com
The strategy lies on the synthesis of liposomes encapsulating opioid drugs which specifically target the inflammatory site. To drive liposomes to the inflammatory site, antibodies targeting adhesion molecules typically upregulated on inflamed endothelial cells (e.g. ICAM-1) are inserted into the lipid bilayer of the particle. The pilot study shows that the delivery of opioid drugs by nanoparticles at the site of inflammation reduces both inflammation and related pain [53]. Compared to peripherally acting opioids, this strategy might be particularly relevant to relieve pain originating from inflammatory foci dispersed all along intestine.
Improvement of local endogenous opioid tone The amounts of opioids released by inflammatory cells entering the site of inflammation within few hours following tissue damage are not sufficient to spontaneously relieve inflammatory pain. However, inflammatory pain may be alleviated by locally injecting exogenous inflammatory mediators such as pro-inflammatory cytokines (IL-1b) or chemokines (CXCL2, CXCL8) [54]. Clinical observations suggest that the intensity of abdominal pain is rather dependent on the type of immune cells at the site of inflammation than the level of inflammation-induced tissue damage by itself. The intensity of visceral inflammatory pain is higher in an environment in which innate immune cells are dominant than in an environment enriched in T lymphocytes [15,16,22]. Thus, triggering the release of endogenous opioids from innate inflammatory cells and improving the migration of effector T lymphocytes into an inflammatory site appear as two complementary therapeutic options. Inflammation is associated with a huge production of proteases including the aminopeptidase N (APN) and neutral endopeptidase (NEP), two peptidases which shorten the half-life of opioid peptides. In order to enhance endogenous control of inflammatory pain by opioids locally produced by immune cells, inhibitors of peptidase activity have been developed. In rats, administration of peptidase inhibitors alleviates from inflammatory pain induced by injecting formalin [55] or complete Freund’s adjuvant [56] into hind paw. Treatment with peptidase inhibitors does not seem to be associated with classical opioid side-effects such as dependence [45] or alteration of locomotor activity and long-term memory [57].
Conclusion The risks related to the chronic use of opioids in intestinal inflammation often overload their beneficial effects. Most of the opioid side effects including nausea, vomiting but also constipation or reduced gastrointestinal motility [58] are at least in part dependent on stimulation of receptors within central nervous system. Given that endogenous opioids produced by intestinal effector CD4+ T lymphocytes as well as exogenous opioid drugs locally applied Current Opinion in Pharmacology 2015, 25:50–55
54 Gastrointestinal
display potent anti-nociceptive and anti-inflammatory properties [59], it can be assumed that an opioid supply restricted to periphery could be instrumental in preventing or reducing IBD flare-ups.
Conflicts of interest Nothing declared.
Acknowledgements This work is supported by the Institut National de la Sante´ et de la Recherche Me´dicale (INSERM), the Universite´ Paul Sabatier, Toulouse III, and the French Agence Nationale de la Recherche grant LYMPHOPIOID.
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