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Drugs of Abuse: Effects on Immunomodulation of Intestinal Ion Transport

Contact Person: David R. Brown (brown013@tc.umn.edu)

Leukocyte-Mediated Intestinal Defenses

The mucous membranes lining the gut, bronchi and other organ systems are in constant contact with the external environment. They share many common structural and functional features which allow them to selectively absorb beneficial substances and vigorously exclude noxious substances, such as microbial pathogens, which might produce systemic infection. Specific host defense in the intestine is mediated by the gut-associated lymphoid tissue (GALT) which comprises the largest mass of immune cells in the body. GALT, which consists of both organized and diffuse lymphoid tissue, mediates immune protection at both local and distant anatomical sites through local dimeric immunoglobulin A (IgA) secretion and the ability of lymphocytes activated at one mucosal site to recirculate and home to other mucosal surfaces (1). The organized GALT functions in antigen presentation to lymphocytes and includes the Peyer's patches (PP) of the small intestine, which in humans and many large animals, occur as single lymphoid foll icles in jejunum and aggregated follicles in ileum. PP function to disseminate immunological information from the gut lumen to mucosal surfaces throughout the body. The specialized epithelium covering these follicles consists of M cells, which are capable of endocytosing and processing luminal antigens for subsequent antigen presentation by underlying follicular dendritic cells, B lymphocytes, and macrophages (2). M cells are also sites of entry for a number of microorganisms, including Gram-negative bacteria such as Shigella, Vibrio, Yersinia and Salmonella, and viruses such as human immunodeficiency virus (HIV), reoviruses and poliovirus; through this route, enteropathogens can invade the lamina propria and infect epithelial cells and mucosal macrophages (2, 3). In the organized GALT, B and T lymphocytes that are activated by antigen presentation, differentiate in germinal centers of lymphoid follicles, rapidly leave the mucosa and circulate in the systemic circulation after passage through the mucosal lymp hatics, then return to the mucosa where they extravasate into either the lamina propria or (in the case of some T cells) the intraepithelial compartment. Most lymphocytes residing in the lamina propria or epithelium that comprise the diffuse GALT are memory cells that mediate cellular and humoral immunity. Humoral immunity in GALT is conveyed by plasma cells committed to IgA synthesis. Polymeric IgA is transported into epithelial cells via secretory component and released into the lumen as secretory IgA (sIgA) where it can neutralize viruses and prevent bacterial adherence to the mucosa; IgA-producing plasma cells can also circulate throughout the lymphatic system and protect other mucosal surfaces (4). Cellular immunity is mediated by T lymphocytes present in the epithelium (i.e. intraepithelial lymphocytes) and lamina propria (5).

The effector function of both the diffuse and organized GALT, as well as neighboring mucosal mast cells and other accessory non-lymphoid cells, appears to be regulated by enteric neurotransmitters (6). Small intestinal PP in pigs are closely associated with submucosal neurons (7). Preliminary investigations in our laboratory suggest that these neurons and their processes may contain acetylcholine and either neuromedin-U or vasoactive intestinal peptide (8). Moreover, immunoreactivity to the cloned delta-opioid receptor and delta-opioid receptor mRNA are present in submucosal neurons adjacent to porcine ileal Peyer's patches; it is likely that this receptor modulates the release of acetylcholine or enteric neuropeptides that in turn regulate aspects of GALT function (9). Interestingly, viruses in the intestinal lumen taken up by M cells over PP may spread to the central nervous system via enteric cholinergic neurons terminating near these lymphoid follicles (10). In rabbit GALT, noradrenergic neurons innerv ate subepithelial regions rich in plasma cells and terminate in interfollicular zones containing large numbers of T-lymphocytes (11). Somatostatin-immunoreactive neurons in cat intestine have been found to terminate in close proximity to PP lymphocytes and plasma cells, and binding sites for the peptide have been detected in the germinal centers of PP and solitary lymphoid nodules of human ileum and colon, respectively (12, 13). Neurons immunoreactive for substance P, vasoactive intestinal peptide, or calcitonin gene-related peptide have been found to project to PP in rodent small intestine (6). These and other neuropeptides alter gut lymphocyte function, proliferation and differentiation, and may affect cellular trafficking in the intestine (14).

There is a close association between intravenous drug use (IDU) and the occurrence of infections caused by HIV and other microorganisms (15). Opium alkaloids can affect the function of both lymphoid and myeloid immune cells, thereby impairing acquired cellular and humoral immune responses as well as innate, non-specific defense processes (16). In many cases, these suppressant actions can be reversed by opioid antagonists such as naloxone, evidence implying that they are mediated by opioid receptors (ORs). Endogenous opioid peptides such as beta-endorphin and enkephalins may be synthesized in lymphocytes, and specific mu-, delta- and kappa-type opioid binding sites have been reported to exist on both lymphocytes and phagocytes (17). The effects of opioids on regional immunity are less well understood and there have been few investigations to examine the presence and actions of opioids in GALT. Opioid abuse is directly associated with some severe intestinal complications, including toxic megacolon, necrotizi ng enterides, and necrotizing angiitis (18). In addition, Gram-negative enteric bacteria have been implicated as causative agents in enterococcal endocarditis and other severe infections associated with opiate abuse; there is evidence that at least a subset of these cases do not involve parenteral inoculation (19). In gastroenterological practice, the use of opioids as antidiarrheal agents is contraindicated in inflammatory colitides (for example, Shigella dysentery, amebiasis, pseudomembranous colitis etc.) because they are associated with enhanced mucosal invasion of enteroinvasive pathogens (20). Because opioid actions on the intestine are not widely viewed in the context of host defense processes in standard pharmacological or medical literature, it is perhaps not surprising there have been no clinical reports in opiate abusers which specifically correlate the frequency of opioid use with enteric infections.

Opium preparations have been employed in the past to render experimental animals susceptible to enteric bacterial infections (21). In this context, opiates were likely given to impair the non-specific defenses of gut motility and fluid secretion (see below), but they may have additionally suppressed GALT function. There are only a few studies that address this latter possibility. Morphine reduces sIgA production in the intestinal tract of mice in response to oral administration of cholera toxin, a potent immunogen (22). The opioid peptide beta-endorphin and the selective delta-opioid agonist oxymorphindole both suppress concanavalin A-stimulated IgA, IgG and IgM production by murine PP T-lymphocytes (23). The milk-derived opioid peptide beta-casomorphin appears to inhibit mitogen-stimulated proliferation of lamina propria lymphocytes from human colon (24) and methionine enkephalin has been reported to enhance colon carcinogenesis (25). Most of these immunosuppressive actions can be inhibited by opioid anta gonists.

Although it is well-appreciated that natural cannabinoids, such as delta9-tetrahydrocannabinol (delta9-THC) and their synthetic counterparts also can decrease disease resistance, there is a paucity of information on whether they can act as co-factors for intestinal infections specifically (26, 27). Cannabinoid binding sites have been detected in the corona of rat intestinal Peyer's patches (28). As cannabinoids can suppress the function of both antigen-presenting cells (such as macrophages) and helper T cells, it is possible that they might reduce humoral immune responses to infection by the intestinal mucosa (29 - 31). Clearly, there is a pressing need for further research in this area.

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Non-immunologic Intestinal Defense

In addition to their accessory role in immune function, columnar epithelial cells of the intestinal mucosa possess the ability to actively absorb and secrete ions, nutrients and water, and they constitute a cellular barrier to subepithelial invasion by luminal pathogens. These are vital protective mechanisms that are under strict physiological control. The active secretion of water and ions by these cells [1] acts to dilute and purge microorganisms or toxins in the bowel, [2] promotes the transfer of sIgA, antimicrobial defensin peptides and mucin into intestinal mucus and the gut lumen and, [3] by affecting intraluminal pH, may alter the growth of enteric microflora. Mucosal secretion is modulated by many enteric neurotransmitters, as well as immune and inflammatory mediators that may affect transport indirectly through their ability to stimulate submucosal neurons (32). Intestinal epithelial cells adhere to each other through a series of junctional complexes. The apical tight junctions (or zonulae occlud ens), which circumferentially belt these cells, have been the focus of intense study because they are disrupted by stress, soluble bacterial products, cytokines and other immune mediators, and various neurotransmitters (32, 33). The density of tight junctions (TJs) is particularly high in the intestinal crypts in relation to villi; in the former location, loosening of TJs probably contributes to paracellular water and Na flux following active transcellular Cl secretion. Furthermore, the transmigration of subepithelial neutrophils into the intestinal lumen, a prominent feature of many disease states, occurs across TJs (34).

Numerous studies in several species (mainly rodents and rabbits) indicate that opioids inhibit mucosal fluid and electrolyte secretion in the small intestine both in vitro and in vivo (35, 36). These antisecretory effects are clearly mediated within the intestine, although we and others have described an additional site of opioid action in the central nervous system (35). Most studies of the direct mucosal actions of opioids have utilized muscle-stripped sheets of ileal mucosa with attached submucosa mounted in Ussing flux chambers. The results of these in vitro studies correlate highly with those conducted at the in vivo level but offer a more precise characterization of the ionic and cellular mechanisms through which these substances act. In isolated mucosal preparations, stable enkephalin analogs rapidly and transiently decrease transepithelial short-circuit current (Isc), a measure of active ion transport, in a naloxone-reversible manner. Measurements of the transepithelial isotopic fluxes of the major extracellular ions sodium and chloride indicate that the opioid-induced change in Isc is due to a reduction in the net secretory flux of chloride ions and an enhancement of salt absorption (35, 36). These changes in mucosal ion transport in vitro are associated with a corresponding reduction in fluid secretion in vivo. Opioid actions are inhibited by the neuronal conduction blocker tetrodotoxin, a result which suggests that these substances act via submucosal neurons (37 - 41). In addition to their actions on spontaneously-secreting tissues, opioids decrease mucosal chloride secretion induced by inflammatory prostaglandins (35). In addition to prostanoids, recent work in our laboratory has revealed that the selective delta-OR agonist [d-Pen2, d-Pen5]enkephalin (DPDPE) dramatically inhibits mucosal Isc responses to histamine and mast cell proteases (trypsin) in porcine ileal mucosa (42, 43). Opioid agonists acting selectively at delta-type ORs tend to display the highest potency and efficacy in decreasing Isc and associated Cl secretion in vitro, although mu-ORs may contribute to these effects (39, 41, 44, 45).

The intestinal antisecretory effects of opioids are generally assumed to be an important component in the antidiarrheal and constipating actions of opioids. However, codeine is a very effective antidiarrheal drug and markedly slows intestinal transit, yet it does not enhance water and electrolyte absorption when given to human subjects (46). Moreover, despite their potential to interact with mu-type ORs in the submucosa, opiate alkaloids have minimal effects on active transepithelial transport of ions in vitro in contrast to enkephalins (35). Because mucosal and submucosal ORs have not been adequately scrutinized, the pharmacological characteristics and regional locations of ORs which impair mucosal secretory defense remain unclear.

There are numerous reports which indicate that opioids produce rapid increases in electrical conductance (Gt) across short-circuited sheets of intestinal mucosa in vitro. For example, submucosally-applied [d-Ala2]Met-enkephalinamide at 1 mM significantly increases Gt by nearly 35% in rabbit ileum (37, 38). Moreover, the mu-opioid agonist [d-Ala2, N-Me-Phe4, Gly5-ol]enkephalin (DAMGO), but not the delta-opioid agonist DPDPE, has been reported to increase Gt by > 30% in mouse jejunal mucosa (39). Opioids have also been found to increase Gt in porcine ileal mucosa (41). This effect of opioids on Gt has generally been overlooked by research workers in the area of intestinal epithelial transport. However, because it is an index of mucosal barrier function, it may have major clinical significance. The intestinal tract contains > 400 species of bacteria which are separated from the intestinal blood supply by a single layer of epithelial cells. A variety of physiological and pathophysiological factors can promote the translocation of enteric bacteria to regional lymph nodes, liver, spleen and other distant sites (47). This phenomenon of bacterial translocation has been identified as a major initiator of sepsis leading to multiple organ failure and is attaining the status of a fundamental concept in critical care medicine (48). The precise mechanisms underlying translocation are largely unknown, although increased mucosal permeability or decreased intestinal motility seem to play a role. The bacteria that migrate most efficiently across the mucosa following suppression of intestinal host defenses or compromises in epithelial barrier function include Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli and Proteus mirabilis (49); these same organisms are present in infections of opiate abusers (50). Subcutaneous infusions or pellet implants of morphine in mice and rats enhance the growth of Gram-negative enteric bacteria in the intestinal lumen and promote translocation of these bacteria to mesenteric lymph nodes and distant sites (51, 52). This action is associated with decreased intestinal transit, but mucosal permeability has not been measured (51). Nothing is presently known about the pharmacological mechanisms by which acute or chronic opioid administration affects mucosal permeability and bacterial translocation.

Like the opioids, cannabinoids can decrease the motility of the small intestine in a species- and drug-dependent manner, thus increasing the contact time of luminal fluids and pathogens with the mucosa (53 - 55). With respect to the intestinal mucosa, high concentrations of delta9-THC have been shown to inhibit enterocyte metabolism and sodium-potassium ATPase activity, necessary components of active ion transport (56, 57). However, there are virtually no published reports of their actions on mucosal transport or epithelial barrier function. We have conducted studies in our laboratory with the highly-potent, non-selective cannabinoid agonists such as HU-210 to address this paucity of information. Our preliminary results suggest that cannabinoids do not affect electrogenic ion transport evoked by inflammatory mediators or electrical field stimulation in the porcine ileal mucosa. These negative results do not, of course, rule out the possibility that cannabinoid activity can be expressed in other species or regions of the gut. Moreover, they do not address the likelihood that cannabinoids alter intestinal immune function.

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Impairments in host defense processes of the intestine due to drug abuse could set the stage for the initiation and spread of bacterial and viral infections, including that of the HIV. Moreover, acute or chronic administration of opioid (and potentially, cannabinoid) analgesic drugs to critically ill or immunocompromised patients may exacerbate preexisting intestinal infections, promote sepsis, or enhance seeding of enteric microorganisms to extra-intestinal sites in the body. Nevertheless, antidiarrheal opioid preparations are indicated for palliative treatment of some AIDS-related diarrheas and opioid analgesic drugs are recommended for the alleviation of pain in immunosuppressed cancer and AIDS patients. Additional research is needed to define the precise mechanisms by which opioids affect innate and acquired immune processes and non-immunological defenses of the intestine in order to mitigate their potential adverse effects in clinical settings.

Marijuana is the most commonly-abused illegal drug in the United States, but interest in its legitimate medicinal use is rapidly growing. However, other than anecdotal reports (58), there is a profound lack of information concerning the actions of cannabinoids in the intestine and their ability to alter the host's susceptibility to intestinal infections. Because they may have either adverse or beneficial effects on the intestinal tract, pharmacological research on the gastrointestinal actions of cannabinoids is urgently needed.

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Brown, D.R.; Poonyachoti, S.; Green, B.; Calvin, A.; Townsend, D.; (1998). Drugs of Abuse: Effects on Immunomodulation of Intestinal Ion Transport. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/
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