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13RESEARCH RESULT
НАУЧНЫЙ РЕЗУЛЬ 7ТТШ
Beskhmelnitsyna E.A., Korokin M.V., Avtina T.V., Martynova O.V., Varavin I.I., Tishin A.N. Ion channel TRPA1 is a promising therapeutic target for treatment of pain. Research result: pharmacology and clinical pharmacology. 2015. Vol. 1, №1 (1): 20-22.
UDC: 615.212
Beskhmelnitsyna E. A.1 Korokin M.V.2 Avtina T.V.3 Martynova O. V.4 Varavin I. I.5 Tishin A.N.6
Pyc. Eng.
DOI: 10.18413/2500-235X-2015-1-4-21-24
ION CHANNEL TRPA1 IS A PROMISING THERAPEUTIC TARGET FOR TREATMENT OF PAIN
1) Gynecologist of Regional State Budget Organization of Health Service 'City hospital №2', 46 Gubkina St., Belgorod,
308036, Russia, e-mail: beskhmelnitsina_e@bsu.edu.ru
2) Doctor of Medical Sciences, Professor; Department of pharmacology, Belgorod State National Research University
85 Pobedy St., Belgorod, 308015, Russia, e-mail: korokin@bsu.edu.ru
3) PhD in Pharmaceutical Sciences, Associate Professor, Department of Pharmacology, Belgorod State National Research University, 85 Pobedy St., Belgorod, 308015, Russia, e-mail: avtina_t@bsu.edu.ru
4) postgraduate student, Department of pharmacology, Belgorod State National Research University, 85 Pobedy St., Belgorod,
308015, Russia, e-mail: myasishcheva@bsu.edu.ru
5) Oncologist of Regional State Budget Organization of Health Service 'Regional Oncological Center', 1 Kuybysheva St.,
Belgorod, 308010, Russia, e-mail: varavin31@yandex.ru
6) postgraduate student, Department of pharmacology, Belgorod State National Research University 85 Pobedy St., Belgorod, 308015, Russia, e-mail: 1068573@bsu.edu.ru
Abstarct. TRPA1 is an ankyrin receptor of TRP family. It is a non-selective, calcium-permeable cation channel that is highly expressed by a subset of small diameter sensory neurons with cell bodies in the dorsal root, trigeminal, nodose and jugular ganglia. In the last time information about the role of TRPA1 in pain and cold sensitivity, as well as in the formation and maintenance of inflammation is increasing in scientific literature. Given this information, the interest for search and study of pharmacological agents, which selectively blocked of TRPA1 and reduced the severity of pain and inflammation is increasing.
Keywords: ion channel TRP; TRPAj; pain; ketorolak, nociception; analgesia; neuropathy.
Pain is a complaint for appeal in the primary healthcare departments, which mainly the load of the treatment of patients with different types of pain syndromes. Besides, costs of treating chronic pain and acute pain relief steadily increase. It is known that about 90% of all diseases are associated with pain [7].
International epidemiological study showed that 49.2% patients of primary healthcare departments had complaint of pain. In according to European epidemiological study 19% of adult Europeans suffer from pain of moderate to severe intensity, which reduces the quality of life, breaking the everyday routine and work. About half of such patients have not received appropriate treatment [4].
According to the Russian Association for the study of pain the prevalence of chronic pain in Russia is average 34.3 cases per 100 persons. More than 40% patients with chronic pain say that pain reduces significantly the quality of their life [1, 2].
Among the approaches used to adjust the use of molecular methods for screening, at the cellular, organ, and organism levels integral.
Today narcotic analgesics and non-steroid anti-inflammatory drugs use for treatment of pain more often. However, both of it have many side effects that limit its widespread and long term use in clinical practice.
Thus, today pharmaceutical market doesn't have analgesic drugs that completely satisfy the requirements of efficiency and safety. That's why the most promising solution is to provide new analgesic drug based on selective inhibition of TRPAi.
TRPA1 is highly expressed by a subset of small diameter sensory neurons with cell bodies in the dorsal root, trigeminal, nodose and jugular ganglia and immediately perceives painful stimuli and inflammatory mediators [6, 81. The results of their research some authors have reported an increase in expression of TRPA1 in pathological conditions, for example, inflammation, neuropathy [3, 5]. Today data is increasingly appearing in the literature on the
RESEARCH RESULT
НАУЧНЫЙ РЕЗУЛЬ
Beskhmelnitsyna E.A., Korokin M.V., Avtina T.V., Martynova O.V., Varavin I.I., Tishin A.N. Ion channel TRPA1 is a promising therapeutic target for treatment of pain. Research result: pharmacology and clinical pharmacology. 2015. Vol. 1, №1 (1): 20-22.
possible use of TRPAi selective inhibitors for treatment of pain syndrome.
The goal of research is study of the analgesic activity of a selective inhibitor of TRPA1 receptors compared with the reference drug ketorolac.
Materials and methods. Experiments were performed on male white laboratory mice weighing 20-22 g. Study of the analgesic activity of TRPAi selective inhibitor was performed in the test «hot plate» in intragastric and intramuscular routes of administration. Ketorolac was used as a comparison drug. Intact animals were placed on a heated to 55 °C plate and fixed the time in seconds before the first lick their paws.
All the animals were divided into 3 groups of each 2 series:
Group I (control): series 1 - intragastric administration of placebo (normal saline) in a volume of 0.1 ml / 10 g body weight (n = 20).
Series 2 - intramuscular injection of placebo (normal saline) in a volume of 0.1 ml /10 g body weight (n = 20).
Group II: series 1 - intragastric administration of ketorolac in a dose of 3.48 mg / kg (n = 20).
Series 2 - intramuscular injection of ketorolac in a dose of 3.48 mg / kg (n = 20).
Group II: series 1 - intragastric administration of TRPAj selective inhibitor (ZB-010621 substance) in a dose of 3 mg / kg (n = 20).
Series 2 - intramuscular injection of TRPA1 selective inhibitor (ZB-010621 substance) in a dose of 3 mg / kg (n = 20).
Then, at 30, 60, 90 and 120 minutes after the administration of substances the animals were placed again at the hot plate and the time in seconds was fixed before the start of the animal licking paws.
Data adequacy of the study were determined by methods of descriptive and analytical statistics with the definition of arithmetical mean (M), their standard mean square error (± m) and P-value (p), calculated using the T-test for groups with different dispersion. Differences were estimated as significant at p <0.05. Statistical calculations were performed using SPSS 21 software.
Results. In intragastric administration of the test substances has been found that a dose of ketorolac 3.48 mg/kg, and TRPAi selective inhibitor (ZB-010621 substance) in a dose of 3 mg/kg exhibit its greatest analgesic activity after 60 minutes from the time of administration (Table 1).
Table 1
The results of «hot plate» test on male white laboratory mice (M±m)
Time Control group Ketorolac group ZB-010621 substance group
intragastric intramuscular intragastric intramuscular intragastric intramuscular
Depature 7.93±0.23 7.7±0.67 7.42±0.49 6.10±0.81 7.60±0.52 8.21±0.81
30 min 8.54±0.72 9.25±0.92 13.57±0.59* 16.41±1.01* 18.81±0.76** 22.19±1.12**
60 min 9.5±0.88 9.73±0.9 15.91±0.61* 13.74±1.16* 21.7±0.82** 19.57±1.43**
90 min 9.75±0.90 8.4±0.71 12.56±0.55 11.82±1.37 17.63±0.79** 17.44±1.79**
120 min 9.39±0.90 8.2±0.70 8.34±0.54 9.21±0.92 13.75±0.71** 14.78±0.92**
Note: * - significant difference from control group (p<0.05), ** - significant difference from Ketorolac group (p<0.05).
However, TRPA1 selective inhibitor (ZB-010621 substance) showed a pronounced analgesic action compared to ketorolac (21.7 ± 0.82 sec and 15.91 ± 0.61 sec, respectively). Moreover, in the group of ketorolac at 90 minutes from the introduction the arithmetical mean of time from the animals were placed on a heated to 55 °C plate till the moment licking paws were not significantly different from the control group (12.56 ± 0.55 sec and 9.75 ± 0.90, respectively), whereas the analgesic effect of a TRPA1 selective inhibitor (ZB-010621 substance) lasted for 90 minutes, and 120 minutes following administration of substance (17.63 ± 0.79 seconds and 13.75 ± 0.71 sec respectively, p <0.05 compared with ketorolac).
In intramuscular administration of the test substances ketorolac and TRPA1 selective inhibitor
(ZB-010621 substance) exhibit analgesic activity maximum at 30 minutes after administration (16.41 ± 1.01 sec and 22.19 ± 1.12 respectively). However, TRPA1 selective inhibitor (ZB-010621 substance) exceeds ketorolac not only in the expression of analgesic activity, but also its duration, as evidenced by the longer time from the moment from the animals were placed on a heated to 55 °C plate till the moment licking paws in the group of TRPA1 selective inhibitor (ZB-010621 substance) compared with the control group after 60, 90 and 120 min, while the action of ketorolac by the ends 90 minutes (Table 1).
Conclusions. Thus, TRPA1 selective inhibitor (ZB-010621 substance) in the «hot plate» test exceeds ketorolac not only in the expression of analgesic activity, but also the duration of its as in
RESEARCH RESULT
НАУЧНЫЙ Р E 3 У Л Ь 7ТТШ
Beskhmelnitsyna E.A., Korokin M.V., Avtina T.V., Martynova O.V., Varavin I.I., Tishin A.N. Ion channel TRPA1 is a promising therapeutic target for treatment of pain. Research result: pharmacology and clinical pharmacology. 2015. Vol. 1, №1(1): 20-22.
intragastric and intramuscular administration of test substances.
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