Inflammation is the immune system response to infection and injury and has been implicated in the pathogeneses of rheumatoid arthritis (RA), stroke, as well as in neurodegenerative and cardiovascular diseases. Tissue injury is usually caused by physical trauma, noxious chemicals, microbial agents, autoimmunity and recruitment of phagocytes, complement system and secretion of cytokines like IL-1?, IL-6 and TNF-? by activated cells, which are essential for the host defense system (Hossain et al., 2010; Dewanjee et al., 2013). Hence, inflammation provides an intrinsically beneficial role in the removal of offending factors and restoration of tissue structure and physiological function (Ricciotti and FitzGerald, 2011).
Inflammatory response could be immunological or non-immunological. Immunological response occurs when immunologically competent cells are activated in response to foreign organisms or antigenic substances liberated during the acute or chronic inflammatory response. Non- immunological response is triggered by inflammatory reactions capable of activating both humoral and cellular systems, normally present in the body in an inactive state and regulated by systemic inhibitors. (Camussi et al., 1981).
When the outer barriers of the skin and other epithelial layers are damaged, the resulting innate responses to infection or tissue injury can induce a complex cascade of events known as the inflammatory response (Owen et al., 2007). Following an injury or sensitization by antigen antibody interactions, inflammatory mediators such as histamine, bradykinin (BK), tryptase, prostaglandins (PGs), leukotrienes (LTs), and platelet activating factor (PAF) produced and released from tissues and mast cells. Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed many pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF?), interleukin-1 (IL-1), IL-6, and chemokines such as IL-8 are abundant in all patients regardless of therapy (Feldmann et al., 2008). Although unchecked inflammatory response leads to painful disorders, the role of biological cytokines should not be under estimated. Potential therapeutic role of TNF? was ascertained in the results obtained from human rheumatoid synovial cultures (Fig.1).
Figure 1: Tumor necrosis factor (TNF) dependent cytokine cascade (Feldman et al., 1996).
Synthesis and release of inflammatory mediators and activation of macrophages, mast cells and dendritic following inflammatory response lead to acute or chronic signs of inflammation. The acute phase of inflammation is characterized by the rapid influx of blood granulocytes, typically neutrophils, followed swiftly by monocytes that mature into inflammatory macrophages that subsequently proliferate and thereby affect the functions of resident tissue macrophages. This process causes the cardinal signs of acute inflammation: redness), heat, swelling) and pain (Ricciotti and FitzGerald, 2011). In the vascular system, acute inflammatory response causes vasodilation and consequent increased vascular flow; increased vascular permeability and leucocytes migration. Histamine and 5-hydroxy tryptamine are usually responsible for eliciting the immediate response of inflammation whereas kinins and prostaglandins mediate the more prolonged delayed onset responses (Shikha et al., 2010).
Through the action of regulatory cytokines such as IL-10, the initiating noxious stimulus is removed via phagocytosis after which the inflammatory reaction is decreased and resolved (Rojas-López et al., 2012; Joshi et al., 2016). Rather than persistence dysfunction which can lead to scarring and loss of organ function, the usual outcome of the acute inflammatory program is successful resolution and repair of tissue damage. It may be anticipated, therefore, that failure of acute inflammation to resolve may predispose to chronic inflammatory disorders such as, rheumatoid arthritis, osteoarthritis, psoriasis, and inflammatory bowel disease (Feldmann et al., 1996; Neogi, 2016).
These inflammatory disorders are identified as a major cause of morbidity worldwide (Dewanjee et al., 2013). Inflammation is usually managed with non-steroidal anti-inflammatory drugs (NSAIDs). However these agents are usually associated with serious adverse effects and their affordability is a concern (Croff, 2013). In chronic pain conditions, for example, the utilization of NSAIDs accompanies severe toxicities including gastric and renal adverse effects (Sostres et al., 2010). Thus the current health care system needs inclusion of newer anti-inflammatory drugs with minimal adverse effect, improved efficacy and at affordable cost
Worldwide, many natural products are used as part of the traditional medical system to control symptoms of inflammatory disorders. Therefore, investigation of natural remedies is required to efficiently control the pain and inflammation with least side effects (Riedel et al., 2015). One way of drug discovery is screening natural products through different animal models (Hossain et al., 2010). Among the different inflammation models, carrageenan induced paw edema model is well-known to investigate the anti-inflammatory activities of various synthetic or natural compounds (Di Rosa et al., 1971; (Halici et al., 2007).
International association for the study of pain (IASP) defines pain as unpleasant sensory and emotional experience associated with actual or potential tissue damage, or describe in terms of such damage (IASP, 1979). Pain serves as a warning of impending injury, triggering appropriate protective response that threatens the integrity of cells or tissues (Bonica, 1979). Chronic pain, however, is a pathological condition that does not serve any useful purpose, but results in a rather substantial loss of quality of life. Indeed, chronic pain is one of the most common and costly health problems (Dubuison, 2006).
On the basis of pathophysiology, pain can be classified as nociceptive and neuropathic. Nociceptive pain is caused by the ongoing activation of A? and C-nociceptors in response to a noxious stimulus and serves a function of indicating real or potential tissue damage (Demerol, 2000).
Activation of the free nerve endings with chemical, physical or noxious thermal stimuli results in release of inflammatory mediators like histamine, calcitonin gene-related peptide (CGRP), BK, serotonin (5-HT), LTs, PGs and, substance P from injured tissues (Fig.2). Then inflammatory mediators will lead to activation or sensitization of nociceptors (Basbun, 2001).
Once sensitization of nociceptors occurs, the action potential generated is propagated through the primary afferent nerve fibers to the spinal cord where they synapse with second order neurons in the grey matter of the dorsal horn. Thereafter, second order neurons from spinal cord project their axons to brain stem or to the thalamocortical system that produces the conscious pain in response to noxious stimuli (Fields and Basbaum, 1978).
Neuropathic pain is caused by aberrant signal processing in the peripheral or central nervous system. After peripheral nerve injury, damaged and non-damaged A and C-fibers begin to generate spontaneous action potentials. Lesions alter the structure and function of the somatosensory nervous system so that pain occurs spontaneously and responses to noxious and innocuous stimuli are pathologically amplified (Latremoliere and Woolf, 2009). Any process that causes damage to the nerves, such as metabolic, traumatic, infectious, ischemic, toxic or immune-mediated pathological conditions, can result in neuropathic pain. In addition, neuropathic pain can be caused by nerve compression or the abnormal processing of pain signals by the brain and spinal cord. Neuropathic pain can be either peripheral (arising as a direct consequence of a lesion or disease affecting the peripheral nerve, the dorsal root ganglion or dorsal root) or central (arising as a direct consequence of a lesion or disease affecting the CNS). However, a clear distinction is not always possible (Ewan and Smith, 2017)
Figure 2:The molecular complexity of the primary afferent nociceptors in response to inflammatory mediators released at the site of tissue injury.
Pain is associated with a number of problems such as, inability to carry out daily activities, feeling of anxiety, depression, anger, or cognitive dysfunction that interfere with the normal physiology and patients’ quality of life and risk of all-cause mortality (Bertin et al., 2016; Da Costa et al., 2016). Left unchecked or inadequate control of these symptoms can contribute to more serious consequences (Kawai et al., 2017).
Prevalence study estimated that 20% of adults suffer from pain globally and 10% are newly diagnosed with chronic pain each year (Goldberg and McGee, 2011). Worldwide, 10 to 15 percent of population is affected by symptomatic osteoarthritis, with 27 and 8.5 million people affected in the United States and United Kingdom, respectively (Neogi, 2016)). Lower back pain (LBP) is also a leading cause of global disability with a global point prevalence of 9.4% (95% CI = 9.0 to 9.8%) (Hoy et al., 2014). A cross-sectional survey conducted in Ethiopia indicated that the mean intensity of migraine in the adult population was 2.6 from which tension type head 2.4%; medication over use headache 2.95; and other headaches 2.6% (Zebenigus, 2017). Another cross-sectional on adult HIV-infected patients in Gonder indicated that the prevalence of pain was 51.2%. Headache (17.9%), abdominal pain (15.6%), and backache (13.3%) were the most common symptoms of study participants (Azagew et al., 2017).
1.3 Management of Pain and Inflammation
Pain conditions, acute or chronic and are treated pharmacologically with a number of drug classes via several routes of administration as drug delivery systems have progressed. These drug classes include, anti-inflammatory drugs, muscle relaxants, antiepileptic medicines, antidepressants, opioids, and local anesthetics (Mathew et al., 2016).
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs in the world. Non-steroidal anti-inflammatory drugs (NSAIDs) belong to a class of drugs; their main benefit derives from their anti-inflammatory and analgesic effect. They act mainly by inhibiting cyclooxygenase (COX) enzymes including COX-1 and COX-2, which are involved in prostaglandin synthesis. This class of medications includes the traditional, non-selective NSAIDs that inhibit both COX-1 and COX-2, and the newer selective COX-2 inhibitors (Baigent et al., 2013). They are highly effective in treating various painful conditions such as osteoarthritis and dysmenorrhea (Asghar and Jamali, 2017). Despite their paramount use in pain management NSAIDs are associated with a number of adverse effects like increased the risk of gastrointestinal (GI) and cardiovascular complications compared with non-NSAID users (Sostres et al., 2010).
Corticosteroids are the most effective anti-inflammatory therapy for many chronic inflammatory diseases, such as asthma. It works by decreasing inflammation and reducing the activity of the immune system (Barnes, 2006; Barnes and Adcock, 2009)). Despite their use as a powerful therapeutic option to treat inflammatory diseases, serious adverse effects were reported including, physiologic and psychiatric adverse drug reactions (ADRs). The most common adverse reactions were upper respiratory tract infections, headache, hypertension, and elevated liver enzymes. Serious infections including tuberculosis, fungal, viral, and other opportunistic infections. Neutropenia and reduction in platelet counts occur occasionally, and demands regular monitoring. GI perforation has been reported when using tocilizumabin patients with diverticulitis or who are using corticosteroids (Warrington and Bostwick, 2006).
Another classes of drugs used in the management of pain are opioids. Opioid analgesics act at cellular level by activating opioid receptors that are found widely distributed in the central nervous system. High levels of opioid receptors are found in the nuclei of tractus solitarius, periaqueductal grey area (PAG), cerebral cortex, thalamus and the substantia gelatinosa (SG) of the spinal cord. Peripheral afferent nerve terminals also contain opioid receptors. Central administration of these analgesic agents produce pronounced effect, but their action is less reliable when applied peripherally like in case of post-traumatic and inflammatory states. Opioid receptor coupling to G-proteins results in closure of voltage sensitive calcium channels and stimulation of potassium efflux. Following receptor stimulation, reduced cyclic adenosine monophosphate production and hyperpolarization occur which could help in the suppression of pain. Overall, the effect is a reduction in neuronal cell excitability that in turn results in reduced transmission of nociceptive impulse (Trivedi et al., 2007).
Despite their use as analgesics from moderate to severe pain, opioids action is limited by the development of dependence and tolerance especially when employed in chronic pain conditions (Martini and Whistler, 2007).
1.4 Traditional Medicine
Pharmaceutical development has led to a great deal of medicines, however many of them are not effective as expected; patients encountered escalating health care costs; and adverse drug reactions are reported in some of the patients. As a result, people showed increased tendency to the use of traditional medicine with an extent not less than 80 % worldwide (Fallis, 2013).
Medicinal plants have been used since ancient times in Africa and viewed as a fundamental component of the traditional healthcare system. In many parts of rural Africa, traditional healers prescribing medicinal plants are the most easily accessible and affordable health resource available to the local community (Tabuti, 2013; WHO, 2015). Besides traditional use, scientific study on medicinal plants provides herbal medicines as a medicinal resource for drug discovery in the future (Asadbeigi et al., 2014).
In Ethiopian traditional medicine a variety of medicinal plants have been used to treat pain and inflammation. These plants include Malva verticillata, Otostegia integrifolia (Getnet et al., 2016), croton macrostchyus (Kamanyi et al., 2009), Ocimum suave (Masresha et al., 2012), Cucumis ficifolius (Teklay et al., 2013), Arisaema schimperianum, Euclea racemose, Malva verticillata (Enyew et al., 2014), Impatients tinctoria (Wolde-mariam et al., 2015), Balanites, Ehretia cymosa (Legese et al., 2015).
1.5 Cucumis ficifolius
Cucumis ficifolius (Cucrbitaceace) is found widely distributed in the East Africa especially in Ethiopia and Kenya. The plant is known locally in Amharic as, ‘yemdir enbuay’, in Tigrigna as, ‘Rambo-ambo’. It is perennial usually with prostrate herb that stems up to 1 m long (Fig. 3). It has finer intermixed spreading hairs; basal stems thickened with light-colored bark, arising from a thickened rootstock (Jeffrey, 1980).
In the Ethiopian folklore medicine, C. ficifolius has traditionally been utilized to treat a number of ailments. In Kilteawlaelo district, Tigray region, Ethiopia, the root of C. ficifolius is chewed with the diseased teeth to treat tooth ache; crushed, filtered and fluid is drunk to treat joint pain; mixed with bark of Croton macrostachyus, the dried paste is mixed with butter and drunk or the product is chewed and then the fluid is drunk to treat stomach ache (Teklay et al., 2013). An ethnobotany study South Gonder, Amhara region showed that the crushed root of C. ficifolius is given to humans, cattles, goat and sheep mixed with milk to treat bloody diarrhea; crushed and powdered then sniffed, drink with coffee cup and fumigated to treat Evil eye; the pilled is chewed and the juice is swallowed/Crushed and drunk with water to treat stomach ache; the affected nail is inserted into the fruits stay until recovery to treat “Lifie” (wound); the shoot is crushed, squeezed and inserted through ear tube to expel ear-mites (Chekole et al., 2015). In the Harla and Dengego valleys, eastern Ethiop, Cucumis dipsaceus is used to treat Gonorrhea, urinary retention and ischuria skin fungus; Cucumis prophetarum is also utilized to treat wound and swollen body part (Belayneh and Bussa, 2104).
Other medicinal plants under the cucurbitaceace has also been used actively as traditional herbal remedies for various diseases. A number of compounds of this group have been investigated for their demonstrated anti-inflammatory, antitumor, hepatoprotective, cardiovascular, immunoregulatory, anti-fungal, anti-bacterial, anti-viral, anti-diabetic, anti-tumor and anti-AIDS activities (Rajasree et al., 2016).
According to a recent report 80% methanol extract of C. ficifolius showed anti-oxidant and hepato-protective activities (Efrem et al., 2017). Some species of the family also exhibited a pharmacologically validated activity. For instance, Cucumis melo extract demonstrated antioxidant and anti-inflammatory properties (Vouldoukis et al., 2004). Previous reports also pointed that the methanolic extract of Cucumis colossus exhibited significant analgesic activity in acetic acid induced writhing test, tail flick and hot plate pain models; it was also indicated in carrageenan acute model that the plant exhibited significant anti-inflammatory activity (Panda et al., 2016).
The phytochemical screening demonstrated C. ficifolius constituted secondary metabolites such as, phenols, flavonoids, terpenoids, steroids and saponins (Efrem et al., 2017) which might confer the plant anti-oxidant and hepatoprotective effects. The diverse biological actions of the Cucurbitaceae family is believed to be due to the presence of different bioactive constituents such as cucurbitacins, triterpenes, sterols, alkaloid, saponins, tannins, flavonoids and phenolic compounds (K. Dhiman, A. Gupta, D. K. Sharma, 2012; Rajasree et al., 2016).
Although C. ficifolius has been used in Ethiopian traditional medicine to treat different ailments, scientific investigation pharmacological actions related to the inflammatory process and pain has not been carried out.
Therefore, the aim of the study was to investigate the anti-inflammatory and anti-nociceptive activities of Cucumis ficifolius
Figure 3:Photograph of Cucumis ficifolius A. Rich.
Pain and inflammation imposes an enormous problem globally. The global prevalence of pain indicated that 20% of adults suffer from pain. The World Health Organization has estimated that 22% of the world’s primary care patients have chronic debilitating pain. Nevertheless, the problem of pain has primarily been regarded as a medical problem, and has been little addressed by the field of public health (Goldberg and McGee, 2011). It is considered a major clinical, social, and economic problem in communities around the world (Henschke et al., 2015; Azevedo et al., 2016).
Pain and inflammatory disorders are associated with a range of deleterious consequences such as, disability, temporary or permanent work discontinuation, reduced quality of life, heightened risk of other physical and mental health comorbidities and greatly increased health care costs, and death (Vietri et al., 2015; Bertin et al., 2016; Kawai et al., 2017)
Thus, any type of pain should be managed with optimal pain relief approaches for optimizing post-operative recovery and reducing morbidity and convalescence. In line with managing pain and inflammation as a target of priority, proposed recommendations such as, weighing the analgesic efficacy and potential risks and provide optimal analgesia with minimal adverse events should be considered (Joshi et al., 2016).
Presently, a number of drug classes are available to manage inflammation and pain. Anti-inflammatory drugs, muscle relaxants, antiepileptic medicines, antidepressants, opioids, and local anesthetics are used through different routes of administration (WHO, 2012; Mathew et al., 2016)
However, the clinical use of anti-inflammatory and analgesic agents is limited by their affordability, accessibility, adverse drug reactions and many medicines are not effective as expected in all patients (Croff, 2013). Another major challenge is development of tolerance and dependence particularly with the chronic use of opioids (Martini and Whistler, 2007).
A meta-analysis comparing the effectiveness of different NSAIDS showed that despite their clinical utility against pain associated with osteoarthritis, their benefit has to be weighed against their potential harmful effects and not all NSAIDS were effective in the pain resolution (Baigent et al., 2013). Diclofenac was superior in efficacy but highly associated with cardiovascular risks (Asadbeigi et al., 2014). Naproxen substantially increased the likelihood of upper gastrointestinal complications (Adebayo et al., 2014). Occurrence of serious adverse effects impedes dose increment according to the extent of pain (Asadbeigi et al., 2014)
Therefore, patients are increasingly interested to explore other options for the disease management using natural products with good effectiveness and fewer side effects. Despite it is inconclusive, herbal medicines are believed and considered to be safe and effective agents as compared to synthetic medicine. Hence people every year turn to use herbal medicine because they believe plant remedies are free from undesirable side effects (Nasri and Shirzad, 2013).
One of the medicinal plants believed to have anti-inflammatory and analgesic activity is Cucumis ficifolius (Cucurbitaceae). In Ethiopia, the plant has been used in the treatment of different ailments including, stomachache, wound, (Chekole et al., 2015); joint pain and tooth ache (Teklay et al., 2013).
Investigation of the plant might contribute for the search of novel bioactive compounds which might serve as a lead compound in the discovery of new analgesic and anti