The Field of the Invention

The invention relates to use of uridine, an endogenous molecule, in the treatment of pain in the pharmaceutical industry and health sector.

Background of the Invention

Pain is a case influencing entire life of a person in physical, spiritual and social aspects. Keeping pain under control provides not only relief of person from the experienced negative feelings but also improvement in life quality. Although non-pharmacologic methods are also used in pain regulation, pharmacologic methods are preferred because of their fast effective strength (Ozveren, 2011). Pharmacologic methods provide pain control by means of preventing transmission of pain sense to central nerveous system or stopping synthesis and release of agents, known as endogen algogenics, such as Substance P, bradykinin, histamine, protons, prostaglandins, leukotrienes, interleukins, tumor necrosis factor alpha (TNF-a), Calcitonin gene-related peptide (CGRP) (Yagci and Saygin, 2019). Main purpose of pharmacologic methods is the application the most appropriate dose, which provides the strongest analgesic effect, causing minimum side effects via the safest and most effective way (Nester and Hale, 2002). In brief, analgesics can be classified as: a. Opioids (narcotics) b. Non-opioid analgesics (non-narcotic analgesics): i. Paracetamol and aspirin ii. Non-steroid anti-inflammatory drugs (NSAIDs).

Use of analgesics unconsciously and in overdoses not only causes some disorders in physiological functions of person but also result in loss for person and country in economic aspect. World Health Organization (WHO) declares that opioid analgesics can be used for effective analgesia provided by them in case of chronic pain. Particularly, it is discovered that it is effective in 70-90% in relief of pains of cancer patients. Constipation, nausea-vomiting, itchiness, respiration depression, motor cognitive disorder, urine retention, delirium, sedation, myoclonus, side effects on immune system, hormonal side effects may occur due to opioid use (Yurugen, 2001). Particularly, development of tolerance by body due to becoming inadequate of narcotic effective (opioid) analgesics dose by time and increase of dose are negative aspects of analgesics (Ozveren, 2011). Use of it is not recommended in post head trauma, during pregnancy, pulmonary functional disorder patients and liver inadequacy.

Despite having analgesic and antipyretic effects, acetaminophen is distinguished from NSAI analgesics because it has too little or none anti-inflammatory effects (Reisli et al., 2021). Its analgesic effectiveness is lower in comparison to NSAI analgesics and opioids. Although not having better analgesic effect in comparison to NSAID it is more convenient for use in terms of its side effects. Where NSAID are not used, they can be included in paracetamol treatment. The fact that it does not have gastrointestinal ulcerogenic effect, nephrotoxicity and platelet disfunction and can be applied both in pregnancy and in children have increased its widely use. (Reisli et al., 2021). In addition, not increasing blood glucose concentration and being discharged through urine are other advantages. However, using in high dose can cause hepatocellular necrosis in livers and acute tubular necrosis in kidneys for elderly and alcoholic individuals (Reisli et al., 2021 ; Lovich-Sapola et al., 2015). Among side effects of acetaminophen use include hypersensitivity to acetaminophen, nausea-vomiting lethargy, sweating, high dose of liver injury or liver failure, encephalopathy, coma and mortality risk (Reisli et al., 2021 ; Gerriets et al., 2018)

NSAIDs reduce prostaglandin release and provide analgesic effectiveness while it may cause occurrence of mucosa damage because prostaglandin is responsible for protecting gastric mucose and such effects increase subject to alcohol consumption. In gastrointestinal system; dyspepsia, gastroduodenal ulcers, hemorrhage and perforation, electrolyte imbalance, sodium retain, glomerular filtration rate reduction, acute renal inadequacy, hypertension, edema, myocardial infarct, stroke and other thrombotic incidents are among side effects of NSAIDs (O’Neil et al., 2012; Reisli et al.., 2021). Particularly, it is not recommended to be used in patients with gastrointestinal lesion, coagulation disorder and pregnants. Apart from these, there are also agents called secondary analgesics, whose main areas of use are other than pain, but which are known to be beneficial in some types of pain. These include antidepressants, neuroleptics, corticosteroids, caffeine and benzodiazepines, N- methyl-D-aspartate (NMDA) receptor antagonists, calcium channel blockers (Onal, 2006). The analgesic effects of the cholinergic system have been known for many years. Increasing the effect of endogenous acetylcholine through direct activation of cholinergic receptors or pharmacological blockade of acetylcholine esterase reduces pain in humans and animals (Yoon et al., 2005; Nicolodi et al., 2002); on the contrary, nociception was found to increase by inhibiting muscarinic cholinergic receptors (Naser and Kuner, 2018). It has been proven that muscarinic agonists (tremorine, pilocarpine, oxotremorine) also produce antinociceptive effects (Bartolini et al., 2011). However direct use of muscarinic receptor agonists is not preferred for providing analgesia because it causes side effects such as bradycardia, hypotension, diarrhea, etc. (Bartolini et al., 2011). Nicotinic receptors, on the other hand, are of great importance in the prevention and treatment of neuropathic pain (Bartolini et al., 2011). The antinociceptive effects of nicotine, which is the main agonist of the nicotinic acetylcholine receptor, have been known for many years (Sahley and Berntson, 1979). The relationship of some known analgesic treatments with the cholinergic system has also been demonstrated. It has been shown that the analgesic effect provided by gabapentin, an important drug for neuropathic pain, is reversed by the administration of a muscarinic receptor antagonist (Hayashida et al., 2007).

In the patent and literature search carried out for the state of the technique, the European patent application with publication number EP3558279 A4 was found. That application generally relates to compounds and compositions for the treatment of chronic pain. Although uridine is mentioned in the compositions, an effect provided by the use alone is not mentioned.

As a result, due to the above-mentioned negativities and the inadequacy of the existing solutions on the subject, it is necessary to make a development in the related technique.

Brief Description of the Invention

The invention has been developed with inspiration from existing situation and aims to eliminate the above-mentioned disadvantages.

The main purpose of the invention is to provide use of uridine, which is an endogenic molecule, in pain treatment in pharmaceutical industry and health sector. The many side effects of analgesics have led to discover/develop new analgesics having no side effects. In this line, idea of using endogenous agents playing a role in pain mechanism in body seems attractive. Uridine is the pyrimidine nucleoside found endogenously in our body (Wurtman et al., 2000). It has been shown that uridine has effects on the synthesis of phospholipids, which are the main components of the cell membrane, on the cholinergic system and on the mechanism of pain. In a study, it was discovered that uridine provides improvement in neurophysiological parameters such as motor conduction velocity (MCV) and sensory conduction velocity (SCV) (Gallai et al., 1992). In another study comparing diclofenac-cholestyramine + uridine + cytidine + vitamin B12 combined treatment with Uridine + cytidine + vitamin B12 control treatment, it was indicated that the combination treatment reduced pain and improved functionality in more patients than the control group (Mibielli et al., 2010). In another study, it was shown by evaluating the visual analog scale (VAS) score that vitamin B12 and nucleotide combination therapy was more effective in reducing the pain of patients than only vitamin B12 therapy (Goldberg et al., 2017). Different from the present invention, uridine was not used alone in these studies, but in combination with other substances. Therefore, it is not possible to say that the analgesic effect obtained depends only on uridine. In two similar studies conducted on patients with peripheral neuropathy (Negrao et al., 2014) and carpal tunnel syndrome (Negrao et al., 2016), uridine monophosphate (UMP) + folic acid + vitamin B12 treatment was applied once a day for 60 days and as a result, a decrease in pain intensity was observed in measured pain scores.

Chronic oral administration of UMP, a membrane phosphatide precursor, has been found to increase acetylcholine level and release in the striatum of old aged rats (Wang et al., 2007). In the study conducted by Cansev et al., the effects of acute uridine administration via intraperitoneal (i.p) route on cholinergic neurotransmission were examined, and it was shown that it increases the release of acetylcholine (Cansev et al., 2015).

Pain is a health problem that concerns many people closely. Due to the limited use of analgesics in some cases, having the side effects of analgesics has led to finding/developing new analgesics with no/less side effects. As a result of previous studies conducted before, it is shown that the activation of the cholinergic system has analgesic effects. However, the results of human and animal studies with uridine are conflicting. It has been observed that cytidine and uridine increase the conversion of choline to cytidine-5-diphosphocholine (CDP-choline) and phosphatidylcholine without affecting basal acetylcholine synthesis in the striatum. This situation reveals results indicating that cytidine and uridine increase cholinergic activation. In the light of this information, it has been proven that the analgesic effect of uridine, which is thought to have few side effects since it is an endogenous molecule in this invention, is dose dependent. It is proven that intraperitoneal administration of uridine at a dose of 1 mmol/kg has an analgesic effect in pain caused by both mechanical and thermal painful stimuli.

The structural and characteristics features of the invention and all advantages will be understood better in detailed descriptions with the figures given below and with reference to the figures, and therefore, the assessment should be made taking into account the figures and detailed explanations.

Brief Description of the Figures

Figure 1 shows Tail Flick Test %MPE values. (n:7, Mean±Standard error; ^### p<0.001 GROUP IA according to the 1 ^st hour, **p<0.01 , “*p<0,001 GROUP IA according to the 2 ^nd hour, ⁺ p<0.05 GRUP IA according to the 3 ^rd hour, ^£££ p<0.001 GRUP IA according to the 4 ^th hour

Figure 2 shows comparison of MPE% hourly values of Tail Flick Test GROUP IVA. (n:7, Mean±Standard error; ⁺⁺⁺ p<0.001 according to the 1 ^st hour, ^### p<0.001 according to the 2 ^nd hour, “p<0.01 according to the 3 ^rd hour).

Figure 3 shows Hot Plate Test %MPE values. (n:7, Mean±Standard error; ^### p<0.001 GROUP IB according to the 1 ^st hour, ***p<0.001 GROUP IB according to the 2 ^nd hour, ⁺⁺⁺ p<0.001 GROUP IB according to the 3 ^rd hour, ^££ p<0.01 , ^£££ p<0.001 GROUP IB according to the 4 ^th hour)

Figure 4 shows comparison of MPE% hourly values of Hot Plate Test Group IVB (n:7, Mean±Standard error; ⁺ p<0.05, ⁺⁺⁺ p<0.001 according to the 1 ^st hour, ^### p<0.001 according to the 2 ^nd hour, ***p<0.001 according to the ^3rd hour).

Figure 5 shows Von Frey Test %MPE values. (n:7, Mean±Standard error; ^## p<0.01 , ^### p<0.001 GROUP IC according to the 1 ^st hour, *p<0.05, ***p<0.001 GROUP IC according to the 2 ^nd hour, ⁺ p<0.05, ⁺⁺⁺ p<0.001 GROUP IC according to the 3 ^rd hour, ^££ p<0.01 , ^£££ p<0.001 GROUP IC according to the 4 ^th hour)

Figure 6 shows comparison of MPE% hourly values of Von Frey Test Group IVC (n:7, Mean±Standard error; ⁺⁺⁺ p<0.001 according to the 1 ^st hour, ^### p<0.001 according to the 2 ^nd hour, ***p<0.001 according to the 3 ^rd hour). Figure 7 shows Plantar Test %MPE values. (n:7, Mean±Standard error; ^# p<0.05, ^### p<0.001 GROUP ID according to the 1 ^st hour, *p<0.05, ***p<0.001 GROUP ID according to the 2 ^nd hour, ⁺ p<0.05, ⁺⁺⁺ p<0.001 GROUP ID according to the 3 ^rd hour, ^£££ p<0.001 GROUP ID according to the 4 ^th hour)

Figure 8 shows comparison of MPE% hourly values of Plantar Test Group IVD (n:7, Mean±Standard error; ⁺⁺⁺ p<0.001 , according to the 1 ^st hour, ^### p<0.001 according to the 2 ^nd hour, ***p<0.001 according to the 3 ^rd hour).

Detailed Description of the Invention

In this detailed description, the preferred embodiments of the invention have been described only for the purpose of better understanding of the matter.

The invention relates to use of an endogenous molecule uridine in pharmaceutical industry and health sector. Specifically, uridine at a dose of 1 mmol/kg is used to be administered intraperitoneally in order to have an analgesic effect in pain caused by mechanical and/or thermal painful stimulus. The formulation used for this purpose composes of uridine.

In the study conducted under the invention, male rates of Sprague Dawley rats, of 250- 350 grams weight and 8-12 weeks old were used. The rats were observed at a 12-hour light/dark cycle, given water and food freely, with 3 rates in each cage in a room of 24- 27 G temperature. The rats were brought to the lab oratory one day before the start of the experiment to enable them to get used to the laboratory environment. After the getting used to period, they were randomly divided into groups with n numbers of 7 in each group.

Drug dosage and Groups:

There were no research that used intraperitoneal uridine in rat experiments on pain. For that reason, firstly, a dose study was performed to determine effective uridine dose. The uridine doses to be administered in the dose study were 0.1 mmol/kg, 0.5 mmol/kg, 1 mmol/kg and 2 mmol/kg. The pain was created by tail flick, hot plate, electronic von Frey and plantar (hargreaves) tests in our laboratory and responses given by rats were recorded. Each rat was subjected to the relevant experiment 2 days before the experiment and the baseline values were recorded. Then, following administration of saline or uridine at different doses (0.1 mmol/kg, 0.5 mmol/kg, 1 mmol/kg, and 2 mmol/kg) on the experiment day, their responses to the same tests at the 1 ^st , 2 ^nd , 3 ^rd and 4 ^th hours were recorded. Tail Flick Test:

Tail-Flick Test developed by D’Armour & Smith in 1941 measures the time period for response by animal given to a thermal painful stimuli given to tail of animal (Deuis et al., 2017). In order to perform this test at our laboratory Plantar/Tail Flick Analgesia Test Device (IITC Model 336, Woodland Hills, CA, ABD) available at laboratory was used. Radiant thermal setting was made by adjustment of light intensity in percentage. Values of parameters indicated as “Active Intensity” and “Idle Intensity” on the device were adjusted as 50% and 10% respectively (Woode et al., 2012). The Idle Intensity value light beam focuses on the determined point of the tail before the test starts, ensuring that the desired region is targeted in each measurement. Since this light value is too low to have a nociceptive effect, it does not affect the measurement. After the Idle Intensity-value light is focused on the point determined for the application, start button was pressed at the desired time and thus the Active Intensity light was directed to the appropriate region. Differently from other value, it is of high value to develop nociceptive effect. In short, while focusing on the appropriate region with Idle Intensity, the nociception required for the test is created with Active Intensity (Minett et al., 2011). Baseline measurements were taken two days before the start of the experiments for this test. Then, on the experiment day, the rats were placed in restricted cages at least 5 minutes before the test time in order to ensure their adaptation. The rats taken onto apparatus and emanating from the radiant heat/light source were focused on the area 5-6 cm away from the tip of the tail. The time (tail flick latency) between when the beam was sent and when the rat withdrew its tail was recorded. The tests were terminated when the rats removed their tails from the heat source or after 10 seconds in order to prevent possible tissue damage regardless of withdrawal of the tail (Kahveci et al., 2011). In order to obtain more convenient data, 3 measurements were conducted at approximately 1 minute intervals and the test result was obtained by taking the average of these 3 measurements.

Hot Plate Test:

The hot plate is a common thermal test that has been used for many years to evaluate nociceptive activity in rodents, and its foundations were discovered in 1944 by Woolfe and Macdonald. Device consists of a heater, timer, plate and a plexiglass chamber. Baseline measurements were taken two days before the start of the experiments for this test. In the experiment firstly, plate surface temperature was adjusted at 52 ± 0.5X3 (Nazeri-Rezaabad et al., 2020). Then, the animal was placed on a metal plate covered with a plexiglass chamber, which kept it in a stable position, and its behaviour was monitored. The time, in seconds, from the first sign of nociception (hind paw withdrawal or licking, jumping) was recorded. If no reaction was observed in the animal, the test was terminated after 30 seconds (Doncheva et al., 2019) in order to minimize the tissue damage that may occur. 3 measurements were taken from each animal at 5 min intervals and the average of these measurements was determined and accepted as the thermal threshold The hot plate method is preferred because it is easy to use, highly reproducible and causes short-term pain (Masocha et al., 2016). Hot-Cold Plate Analgesia Tester (IITC Model PE34, Woodland Hills, CA, USA) was used for the experiments.

Electronic von Frey Test:

In the electronic von Frey test (IITC Model 2290, ELECTROVONFREY, Woodland Hills, CA, USA), a single rigid filament is applied with increasing force until the daw hind paw withdrawal response occurs, and the paw withdrawal threshold is automatically recorded. (Deuis et al., 2017). Baseline measurements were taken two days before the start of the experiments for this test. Before starting experiment adaptation period was provided to prevent confusion of discovery behaviour of animal with response given by it to the pain stimuli. In order to allow adaptation, rats were put in plexiglass chambered with mesh floor 15 minutes before the test in a manner each rat was in different chamber. After 15 minutes hind paw plantar surface was exposed to a force by use of a 0.5 mm diameter polypropylene hard tip and force at which aw paw withdrawal occurred was automatically recorded by the device. In order to obtain more certain data the test was repeated 3 times for minimum 10 seconds for each rat and average of measurements was taken (Kahveci et al., 2011). The obtained value was recorded as mechanic pain threshold of the rat.

Plantar Test (Hargreaves Test Method):

A thermal stimulus from a radiant heat/light source is focused on the plantar surface of the rat’s hind paw with this test, and after this stimulus, the latency of the rat's paw withdrawal is measured. In order to perform this test at our laboratory Plantar/Tail Flick Analgesia Test Device (IITC Model 336, Woodland Hills, CA, ABD) available at laboratory was used. Test device has 2 folded structures. Chamber dividing folds consist of glass surface. Thus, plantar surfaces of rats placed in appropriate chamber in upper part could be easily monitored by help of an angular mirror located onto radiant heat/light source placed in lower part. Radiant thermal setting was made by adjustment of light intensity in percentage. Values of parameters indicated as “Active Intensity” and “Idle Intensity” on the device were adjusted as 50% and 10% respectively (Woode et al., 2012). In this line idle intensity value light beam was focused onto the determined point of back paw and thus it was targeted to provide a proper directing. After the Idle Intensity-value light was focused on the point determined for the application, start button was pressed at the convenient time and thus the Active Intensity light was directed to the appropriate region. Baseline measurements were taken two days before the start of the experiments for this test. Then following determination of desired point by guide light source on experiment date, light beam was sent to 4x6 mm area. Light intensity was set at a convenient level to prevent tissue damage and cut off period was set as 25 seconds (Aykan et al., 2019). The time until the paw retraction reaction of rat as per the created pain sense was measured and this operation was repeated 3 times at 3 minutes intervals. Average of obtained measurement results was computed and thermal pain threshold was estimated (Kahveci et al., 2011).

Results of study performed under scope of the invention show that 1 mmol/kg uridine to be applied intraperitoneally can have analgesic effect because of increasing pain threshold against both thermal and mechanical pains at the 2 ^nd hour.

The data of the conducted analysis were calculated in %MPE (Maximum potential effect percentage) = [(threshold measured after drug - (baseline) threshold measured before drug I (cut off value - threshold value (baseline) measured before drug)] x 100 and presented in graphics.

Tail Flick Test %MPE Values (Fiqure 1 and Fiqure 2):

• No statistical difference was discovered upon comparison of 1 ^st , 2 ^nd , 3 ^rd and 4 ^th hours of Group IA rats given saline. For that reason each hour of those rats to which saline was administered was used as control group of same hours of other groups and statistical comparisons were made accordingly. • Values of GROUP IVA rats given 1 mmol/kg uridine and GROUP VA rats given 2 mmol/kg uridine are better when compared to value of saline administered Group IA rats at the first hour (p<0.001).

• While values of GROUP HA rats given 0.1 mmol/kg uridine and GROUP IIIA rats given 0.5 mmol/kg uridine are worse when compared to value of saline administered Group IA rats at the 2 ^nd hour (respectively; p<0.01 , p<0.001 ), 1 mmol/kg uridine administered GROUP IVA and 2 mmol/kg uridine administered GRUP VA rats values are better (p<0.001).

• Values of GROUP IVA rats administered 1 mmol/kg uridine are better when compared to value of GROUP IA rats administered saline at the 3 ^rd hour (p<0.05).

• Values of GROUP HA rats administered 0.1 mmol/kg uridine are worse when compared to value of GROUP IA rats administered saline at the 4 ^th hour (p<0.001).

• When data are assessed in general, time period to respond to pain stimulus were compared to baseline value and only value of rates of GROUP IVA were found significant. For that reason, hourly values in %MPE of Group IVA administered 1 mmol/kg uridine were compared. As a result of the comparisons, it is discovered that values at the 1 ^st , the 3 ^rd and the 4 ^th hours are shorter when compared to the 2 ^nd hour one. (p<0.001).

Hot Plate Test %MPE Values (Figure 3 and Figure 4):

• No statistical difference was discovered upon comparison of 1 ^st , 2 ^nd , 3 ^rd and 4 ^th hours of Group IB rats given saline. For that reason, each hour of those rats to which saline was administered was used as control group of same hours of other groups and statistical comparisons were made accordingly.

• While values of GROUP HB rats given 0.1 mmol/kg uridine are worse when compared to value of saline administered Group IB rats at the 1 st hour (p<0.001) values of GROUP IVB given 1 mmol/kg uridine and GROUP VB rats given 2 mmol/kg uridine are better (p<0.001).

• While values of GROUP HB rats given 0.1 mmol/kg uridine and GROUP IHB rats given 0.5 mmol/kg uridine are worse when compared to value of saline administered GROUP IB rats at the 2 ^nd hour (p<0.001), values of 1 mmol/kg uridine administered GROUP IVB and 2 mmol/kg uridine administered GROUP VB rats are better (p<0.001 ).

• While values of GROUP I IB rats given 0.1 mmol/kg uridine, values of GROUP I IIB rats given 0.5 mmol/kg uridine are worse when compared to value of saline administered GROUP IB rats at the 3 ^rd hour (p<0.001), values of GROUP VB given 2 mmol/kg uridine are better (p<0.001).

• While values of GROUP IIIB rats given 0.5 mmol/kg uridine are worse when compared to value of saline administered Group IB rats at the 4 ^th hour (p<0.001) values of GROUP IVB given 1 mmol/kg uridine and GROUP VB rats given 2 mmol/kg uridine are better (respectively; p<0.001 , p<0.01).

• When data are assessed in general, time period to respond to pain stimulus were compared to baseline value and only value of rates of GROUP IVB were found significant. For that reason, hourly values in %MPE of GROUP IVB administered 1 mmol/kg uridine were compared. As a result of the comparisons, it is discovered that values at the 1 ^st , the 3 ^rd and the 4 ^th hours are shorter when compared to the 2 ^nd hour one (respectively p<0.05, p<0.001 , p<0.001).

Von Frey Test %MPE Values (Figure 5 and Figure 6):

• No statistical difference was discovered upon comparison of 1 ^st , 2 ^nd , 3 ^rd and 4 ^th hours of GROUP IC rats given saline. For that reason, each hour of those rats to which saline was administered was used as control group of same hours of other groups and statistical comparisons were made accordingly.

• While values of GROUP IIC rats given 0.1 mmol/kg uridine, GROUP IIIC rats given 0.5 mmol/kg uridine and GROUP VC rats given 2 mmol/kg uridine are worse when compared to value of saline administered GROUP IC rats at the 1 ^st hour (respectively p<0.001 , p<0.01 , p<0.001), values of GROUP IVC rats given 1 mmol/kg uridine are better (p<0.001 ).

• While values of GROUP IIC rats given 0.1 mmol/kg uridine and values of GROUP VC rats given 2 mmol/kg uridine are worse when compared to value of saline administered GROUP IC rats at the 2 ^nd hour (respectively, p<0.05, p<0.001), values of GROUP IVC given 1 mmol/kg uridine are better (p<0.001). • While values of GROUP IVC rats given 1 mmol/kg uridine are better when compared to value of saline administered GROUP IC rats at the 3 ^rd hour (p<0.05), values of GROUP VC rats given 2 mmol/kg uridine are worse (p<0.001).

• Values of GROUP IIC rats given 0.1 mmol/kg uridine, values of GROUP HIC rats given 0.5 mmol/kg uridine and values of GROUP VC rats given 2 mmol/kg uridine are worse when compared to value of saline administered Group IC rats at the 4 ^th hour (respectively p<0.01 , p<0.001 , p<0.001).

• When data are assessed in general, time period to respond to pain stimulus were compared to baseline value and only value of rates of GROUP IVC were found significant. For that reason, hourly values in %MPE of Group IVC administered 1 mmol/kg uridine were compared. As a result of the comparisons, it is discovered that there is no difference from the values at the 1 ^st hour when compared to the 2 ^nd hour value but the values at the 3 ^rd and the 4 ^th hours are lower (p<0.001).

Plantar Test %MPE Values (Figure 7 and Figure 8):

• No statistical difference was discovered upon comparison of 1 ^st , 2 ^nd , 3 ^rd and 4 ^th hours of Group ID rats given saline. For that reason, each hour of those rats to which saline was administered was used as control group of same hours of other groups and statistical comparisons were made accordingly.

• While values of GROUP HID rats given 0.5 mmol/kg uridine are better when compared to value of saline administered GROUP ID rats at the 1 ^st hour (p<0.05), values of GROUP VD rats given 2 mmol/kg uridine are worse (p<0.001).

• While values of GROUP HD rats given 0.1 mmol/kg uridine are worse when compared to value of saline administered Group ID rats at the 2 ^nd hour (p<0.05), values of GROUP HID given 0.5 mmol/kg uridine and GROUP IVD rats given 1 mmol/kg uridine are better (p<0.001).

• Values of GROUP HD rats given 0.1 mmol/kg uridine, values of GROUP HID rats given 0.5 mmol/kg uridine and values of GROUP IVD rats given 1 mmol/kg are better when compared to value of saline administered Group ID rats at the 3 ^rd hour (p<0.001 , p<0.05, p<0.001).

• While values of GROUP HD rats given 0.1 mmol/kg uridine are worse when compared to value of saline administered GROUP ID rats at the 4 ^th hour (p<0.001), values of GROUP HID given 0.5 mmol/kg uridine and GROUP IVD rats given 1 mmol/kg uridine are better (p<0.001).

• When data are assessed in general, time period to respond to pain stimulus were compared to baseline value and only value of rates of GROUP IVD were found significant. For that reason, hourly values in %MPE of Group IVD administered 1 mmol/kg uridine were compared. As a result of the comparisons, it is discovered that values at the 1 ^st , the 3 ^rd and the 4 ^th hours are shorter when compared to the 2 ^nd hour one (p<0.001 ).

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