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Targeting opioid signaling in Crohn’s disease: new therapeutic pathways
Expert Rev. Gastroenterol. Hepatol. 5(5), 555–558 (2011)
“The exciting discovery that endogenous opioids and opioid receptors form a tonically active inhibitory signaling pathway that regulates cell proliferation ... has provided an innovative and unconventional hypothesis in understanding the pathophysiology and treatment of autoimmune diseases such as Crohn’s disease.”
Ian S Zagon
Author for correspondence: Department of Neural & Behavioral Sciences,
The Pennsylvania State University College of Medicine, 500 University Drive, H109, Hershey,
PA 17033, USA
Tel.: +1 717 531 8650 Fax: +1 717 531 5003
[email protected]
Patricia J
McLaughlin
Department of Neural & Behavioral Sciences,
The Pennsylvania State University College of Medicine, 500 University Drive, H109, Hershey, PA 17033, USA
Crohn’s disease (CD) is a chronic inflammatory condition of the GI tract with no known cause or cure, and treatment modalities largely focus on controlling the inflammatory response. The exciting discovery that endogenous opioids and opioid receptors form a tonically active inhibitory signaling pathway that regulates cell pro- liferation, including suppression of T and B lymphocyte responses, has provided an innovative and unconventional hypothesis in understanding the pathophysiology and treatment of autoimmune diseases such as CD. The opioid growth factor (OGF; [Met5]-enkephalin)–opioid growth factor receptor (OGRr) axis is a probable candi- date to become a key endogenous pathway in the pathogenesis and treatment of CD. Strategies that upregulate the function of the OGF–OGFr system, such as low- dose naltrexone (LDN), hold considerable promise in designing new biological-based treatments that are efficacious, nontoxic, inexpensive and orally delivered.
Crohn’s disease, along with ulcerative colitis, are chronic inflammatory disor- ders of the GI tract, conditions collectively termed inflammatory bowel disease (IBD). With a prevalence of 100–200 per 100,000 in Europe and North America, IBD accounts for a lower quality of life and marked morbidity for patients [1,2]. Although CD presents at any age and is most often diagnosed in adults in their 20s and 30s, approximately 30% of the 400,000–600,000 CD patients in the USA develop symptoms before 20 years of age. Along with the human toll, the economic burden of CD has been estimated to be US$10–15 billion in the USA and €2–16 billion in Europe [3]. The etiology of CD is unknown, but research suggests it involves a complex interplay of microbial, environmental, immunological and genetic variables [4]. One prevailing theory regarding the pathogenesis of CD is “that this disease is the result of a dysregulated immune response to intestinal microflora in the setting of a genetic predisposition and conditioning environmental fac- tors” [4].
Traditionally, treatment of CD has been directed at controlling symp- toms, maintaining remission and prevent- ing relapse. Therapies include compounds designed to reduce the inflammatory response, such as the 5-aminosalicylate compounds, corticosteroids, immuno- modulators (e.g., methotrexate), as well as the development of novel immuno- therapies (e.g., TNF, IL-2 and IL-10) [5]. However, patients with CD often experience flares of disease activity, not to mention side effects from toxicity [5]. Thus, there is an urgent unmet medical need to understand the pathogenesis and treatment of CD.
“Strategies that upregulate the function of the opioid growth factor–opioid growth factor receptor system, such as low-dose naltrexone, hold considerable promise in designing new biological- based treatments that are efficacious, nontoxic, inexpensive and orally delivered.”
Opioid peptides, opioid receptors & cell proliferation
Neuropeptides are defined as any peptide released from the nerv- ous system that serves as an intercellular signaling molecule, and these have been thought to play a role in IBD [6]. However, neuro- peptides also are known to be produced, secreted and function in non-neural cells. One case in point is the endogenous opioid peptides (enkephalins and endorphins) and their receptors that can regulate a variety of non-neural and neural physiological processes, including serving as a gatekeeper of the pace of cell proliferation through tonically active inhibitory signaling path- ways [7]. Endogenous opioids and opioid receptors are present in the GI tract and can modulate immune responses [7–11]. Indeed, mice with an absence of preproenkephalin, the precursor to the opioid peptide [Met5]-enkephalin, exhibit an increased threshold for T-cell activation [12].
Modulation of opioid peptide–opioid receptor interactions with LDN
If CD is a result of an T- and B-cell acceleration, a feasible approach worthy of consideration is to treat this disease by ele- vating the endogenous opioid–opioid receptor system in order to take advantage of its repressive action on cellular accumula- tion and immune activation. One way to upregulate the endog- enous opioids and opioid receptors is to use the strategy of a rebound effect following administration of opioid antagonists such as naltrexone (NTX) [13–15]. It has long been known that opioid antagonists block the opioid receptors from interacting with endogenous opioids, leading to a compensatory increase of both opioids and receptors in an attempt to overcome the disengaging of opioid peptides from their receptors and regain function. An important discovery was made that a short dura- tion of opioid antagonist exposure (e.g., 4–6 h/day) allows for an extended interval (18–20 h/day) wherein the increased opioids and opioid receptors can interact and produce an exaggerated effect: depression of cell proliferation [15].
Clinical trials of LDN & CD
Collaboration of basic and clinical scientists have tested the theory that LDN would be therapeutic for CD, with the idea that there is a deficiency in opioid peptide–opioid receptor interactions in CD that can be restored to homeostatic levels by upregulating the endogenous opioid systems. In an open-labeled study [16], patients having active CD (CD activity index [CDAI] of 356) were given 4.5 mg of LDN orally daily. CDAI scores decreased significantly with LDN and remained lower than baseline 4 weeks after com- pleting a 12-week therapy. A total of 89% of the patients exhibited a response to therapy and 67% achieved a remission. Improvement was recorded in both quality of life surveys with LDN compared with baseline. No laboratory abnormalities were recorded, with the most common side effects being disturbances in sleep.
In a follow-up study, a randomized, double-blind, placebo- controlled investigation tested the efficacy and safety of LDN for 12 weeks in adults with active CD [17]. More than twice as many patients (88%) taking LDN exhibited a 70-point decrease in CDAI scores, in contrast with only 40% of individuals in the placebo group. Likewise, 63% of patients in the LDN group and only 33% of individuals subjected to placebo achieved the more stringent criteria of a 100-point decline in CDAI scores. As a secondary outcome, mucosal healing (endoscopy and histo- pathology) was also assessed in these studies. At 12 weeks, 78% of the patients receiving LDN, but only 28% of patients subjected to placebo, had a 5-point decline in the CD endoscopy index severity score (CDEIS) from baseline values. The data gathered in this study also revealed that 33% of the patients on LDN had remission (a CDEIS score of <6) in contrast to only 6% of the patients in the placebo group.
Interpretation of results & mechanistic explanation
Since NTX is a general opioid receptor antagonist that is devoid of intrinsic activity and blocks opioids from opioid receptors [18], these results provide evidence that endogenous opioid systems are dysfunctional in CD – either as a primary problem or secondary to other issues. This leads to the conjecture that a diminishment in endogenous opioid peptide(s) and/or opioid receptor(s) in CD forms a critical contribution to escaping normal regulation of physiological processes in the GI tract and the expression of dis- ease. These data also suggest that correction of opioid peptide–opi- oid receptor interactions even in the midst of active disease can restore homeostasis and reverse the pathobiology of CD.
How can these data be interpreted in light of our knowl- edge about signaling between endogenous opioids and opioid receptors? Moreover, is there a cellular and molecular basis that provides a unifying concept for understanding how CD, LDN and endogenous opioids/opioid receptors relate to one another? Evidence from basic biomedical research may provide answers. First, NTX enters cells by a process of passive diffusion [19], thereby gaining immediate access to cells and modifying cel- lular function. Second, the mechanism of LDN on cell prolif- eration has recently been elucidated at the molecular level, and the OGF–OGFr is the target for this specific opioid antagonist action [15]. Using a novel model of short-term opioid receptor blockade in tissue culture that closely parallels LDN action in vivo, LDN was shown to inhibit cell proliferation in the face of silencing the other classical opioid receptors: μ, d and k. However, LDN was ineffective when OGFr was silenced by siRNA. Moreover, only one opioid peptide – OGF – was found to depress cell proliferation when a wide variety of synthetic opioids (including those selective for μ, d, k and OGFr receptors) were tested. When OGF was neutralized by antibodies specific to this peptide, the effects of LDN on depressing cell proliferation were not observed. Finally, the mechanism of LDN required p16 and/or p21 cyclin-dependent inhibitory kinases that target the G1/S phase of the cell cycle. These characteristics are all hallmarks of the OGF–OGFr pathway [7,15,20].
Given that opioid signaling, and in particular OGF, is impor- tant to the course of CD as well as other autoimmune diseases (e.g., multiple sclerosis), and that modulation of the OGF–OGFr axis by LDN, as in the case of CD, or by OGF or LDN for experimental autoimmune encephalomyelitis (a model for multi- ple sclerosis), can attenuate autoimmune diseases, the relationship of OGF to the immune response needs to be addressed. CD and other autoimmune diseases are widely thought to be related to T-cell-mediated immunity, although there is evidence for humoral immunity in the disease process by an antigen-driven B-cell response. T and B cells depend on proliferation for response and OGF depresses T- and B-cell proliferation by an OGFr-dependent inhibitory pathway involving p16 and p21 [21,22]. As added evi- dence that opioid antagonists do not have a direct effect on immune response, continuous opioid receptor blockade by NTX has no effect on T- or B-cell proliferation. These data also indi- cate that these splenic-derived cell types – unlike all other cells examined to date – are not tonically regulated by the OGF–OGFr axis. This may be due in large part because only small amounts of preproenkephalin-derived peptides, which require dibasic cleavage for formation of smaller peptides (e.g., OGF) and are the opioid-active forms, have been recorded in T lymphocytes. However, the OGFr has been documented in T and B cells, and this peptide is fully capable of inhibiting cell proliferation through p16 and p21 cyclin-dependent inhibitory kinase pathways [21,22].
Commentary & future perspective
Crohn’s disease is a chronic, devastating disease that is long term and persistent, and without any fully effective prevention or treat- ment. Compelling studies in basic science have given rise to an exceptionally innovative and unconventional hypothesis that is substantially different from mainstream ideas regarding CD research. The evidence that irregularities in endogenous opioid systems appear to be a mechanistic explanation for the progression of CD provides an entirely new paradigm regarding the patho- physiology and attending adverse outcomes of CD (and IBD). If also offers the opportunity for a biological-based approach in the restoration to a homeostatic condition. This discovery has already provided the capability to translate these new ideas to the patient, and the clinical studies conducted thus far have provided exciting and provocative results that promise even greater rewards.
On the horizon, we need more basic knowledge about the rela- tionship of endogenous opioid systems and CD in order to not only provide direction to clinical studies but also to devise bio- markers for the efficacy of treatment with the OGF–OGFr axis. It is interesting that two studies have reported an association between locus 20q13 in pediatric-onset CD [23,24] and IBD [23], and another report relates this same locus to ulcerative colitis [25]. Since OGFr is located at 20q13.3, this raises the question of whether there is any relationship between chromosomal variation and CD. On a different note, there are a number of means to modulate the OGF–OGFr axis [26]. Besides LDN, the imidazoquinoline com- pound imiquimod, which has potent antiviral and anti-tumor properties, has a mechanism dependent on upregulation of OGFr that ultimately leads to a robust OGF–OGFr interaction [27,28]. In addition, exogenous OGF, already shown to be nontoxic and efficacious in cancer [26] and experimental autoimmune encephalo- myelitis [29], may serve as equal or even superior means to treat CD. Ultimately, such a focus on the pathobiology of CD and treating the cause rather than symptoms will be an extraordinary outcome of these new findings in benefiting patient care.
Financial & competing interests disclosure
Ian Zagon has intellectual property rights and a patent for the use of nal- trexone in IBD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
“...a feasible approach worthy of consideration is to treat this disease by elevating the endogenous opioid–opioid receptor system in order to take advantage of its repressive action on cellular accumulation and immune activation.”
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