WO2014175518A1 - Composition pour soulager, prévenir ou traiter la douleur contenant de l'extrait de maté comme principe actif et procédé pour évaluer l'efficacité du soulagement, de la prévention ou du traitement de la douleur d'un échantillon - Google Patents

Composition pour soulager, prévenir ou traiter la douleur contenant de l'extrait de maté comme principe actif et procédé pour évaluer l'efficacité du soulagement, de la prévention ou du traitement de la douleur d'un échantillon Download PDF

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Publication number
WO2014175518A1
WO2014175518A1 PCT/KR2013/008702 KR2013008702W WO2014175518A1 WO 2014175518 A1 WO2014175518 A1 WO 2014175518A1 KR 2013008702 W KR2013008702 W KR 2013008702W WO 2014175518 A1 WO2014175518 A1 WO 2014175518A1
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Prior art keywords
pain
composition
present
sample
animal
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PCT/KR2013/008702
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English (en)
Korean (ko)
Inventor
김윤태
한대석
김재구
이창호
김인호
조승목
Original Assignee
한국식품연구원
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Priority claimed from KR20130044944A external-priority patent/KR101483990B1/ko
Priority claimed from KR1020130044943A external-priority patent/KR101500485B1/ko
Application filed by 한국식품연구원 filed Critical 한국식품연구원
Publication of WO2014175518A1 publication Critical patent/WO2014175518A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61D—VETERINARY INSTRUMENTS, IMPLEMENTS, TOOLS, OR METHODS
    • A61D7/00—Devices or methods for introducing solid, liquid, or gaseous remedies or other materials into or onto the bodies of animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • the present invention relates to a composition for the relief, prevention or treatment of pain, comprising a mate extract as an active ingredient, and a method for evaluating the efficacy of pain relief, prevention or treatment of a sample.
  • the present inventors have found that a safe substance for a human body that can effectively alleviate i pain, in particular plant-was intensive studies seek to develop derived materials, and as a result to the mate that is being used as the primary raw material in the conventional relief, preventing or treating pain in a very It was found to be valid.
  • an object of the present invention is to provide a composition for preventing or treating pain relief.
  • Another object of the present invention to provide a food composition and pharmaceutical composition for the relief, prevention or treatment of pain.
  • composition of the present invention when administered to an animal prior to skin incision surgery, the pain sensitivity at the surgical site was decreased and the composition of the present invention was administered to an animal with nerve branch ligation injury. , Pain sensitivity decreased.
  • composition of the present invention exhibits a significant pain relief effect through oral administration rather than intravenous injection or skin application.
  • the composition of the present invention having these characteristics can be well applied to food.
  • the composition of the present invention not only has a palliative and therapeutic effect on the previously generated pain, but also has an effect of preventing pain when administered to a subject before the pain occurs.
  • Mate Ilex paraguayensis used as an active ingredient in the composition of the present invention is a plant belonging to the persimmon tree as an evergreen subfamily of persimmon tree.
  • Suitable as nonpolar solvents are acetone, acetonitrile, ethyl acetate, methyl acetate, fluoroalkane, pentane, nucleic acid, 2, 2,4-trimethylpentane, decane, cyclonucleic acid, cyclopentane, diisobutylene, 1- Pentene, 1-chlorobutane, 1-chloropentane, 0-xylene, diisopropyl ether 2-chloropropane, toluene, 1-chloropropane, chlorobenzene, benzene, diethyl ether, diethyl sulfide, chloroform, dichloro Methane, 1,2-dichloroethane, anneal, diethylamine, ether, carbon tetrachloride and THF.
  • the extraction solvent used in the present invention is (a) water, (b) anhydrous or hydrous lower alcohol having 1 to 4 carbon atoms (methane, ethane, propane, butanol, etc.), ( c) a mixed solvent of the lower alcohol and water, (d) acetone, (e) ethyl acetate, (f) chloroform, (g) butyl acetate (h) 1,3-butylene glycol, (i) hexane and (j) diethyl ether.
  • the extraction solvent used in the present invention is water, ethanol or a combination thereof. According to a particular embodiment of the present invention, the extraction solvent used in the present invention is 4 ()-80 vol% grain alcohol.
  • the mate extract of the present invention is obtained by adding alcohol to the mate leaves, followed by filtration and concentration under reduced pressure, followed by lyophilization.
  • Mate extract used in the present invention may be prepared in a powder state by an additional process such as vacuum distillation and freeze drying or spray drying.
  • the term 'extract' has the meaning commonly used as a crude extract in the art as described above, but also broadly includes a fraction additionally extracting the extract. That is, the mate extract is not only obtained by using the above-described extraction solvent, but also includes one obtained by additionally applying a purification process. For example, a fraction obtained by passing the extract through an ultrafiltration membrane having a constant molecular weight cut-off value, separation by various chromatography (manufactured for separation according to size, charge, hydrophobicity or affinity), etc. The fraction obtained by the method is also included in the mate extract of the present invention.
  • nociceptive pain is used to encompass all pain caused by harmful stimuli that may damage or actually damage body tissues, including cuts, bruises, Pain without bone fracture, crush injury, burn and similar wounds, without limitation. Pain receptors for tissue damage (nociceptors) are mostly located in the skin, musculoskeletal system or internal organs.
  • pain is used to refer to pain that occurs in bones, joints, muscles, skin or connective tissue. This type of pain is typically very local.
  • visceral pain is used herein to refer to respiratory, gastrointestinal tract and pancreas in intestinal organs, urinary tract and reproductive organs. Used to indicate pain that occurs. Visceral pain includes pain induced by tumor involvement of the organ capsule. Other types of visceral pain are typically characterized by intermittent cramping and severe local pain caused by obstruction of the hoi low viscus. Visceral pain may be associated with inflammation as in the case of cystitis or reflux esophagit is.
  • “superficial pain” refers to pain felt along the skin segment in which the nerves of the dorsal root are distributed, and is a direct pain that feels pain at the point of stimulation.
  • Deep pain refers to pain originating from deep organs and differs in the nature and extent of pain depending on the nature of the tissue. Particularly sensitive to pain are tendons, deep muscles, ligaments, joints, periosteum, blood vessels and nerves. In general, deep pain is a sensation that is dull and spread around. Deep and internal pain, such as the complex mechanism of the pain is difficult to find the location of the pain, nausea, sweating, increased blood pressure also appears.
  • neuroopathic pain is used herein to refer to pain resulting from sensory input of abnormal processing by the peripheral or central nervous system resulting from peripheral or central nervous system disorders.
  • procedural pain refers to pain that occurs in a medical, dental or surgical procedure, which procedure is usually scheduled or associated with acute trauma.
  • itch is used herein in a broad sense and refers to all types of itchy and stinging sensations of acute intermittent and persistent, which can be generally explained locally.
  • the itching may be idiopathic, allergic, metabolic, infectious, drug-induced, liver, kidney disease or cancer.
  • Pruritus is severe itching.
  • the composition of the present invention works very effectively to alleviate, prevent or treat persistent peripheral neuropathic pain.
  • composition of the present invention When the composition of the present invention is prepared as a food composition, it contains not only mate extract as an active ingredient, but also components commonly added in food production, and include, for example, proteins, carbohydrates, fats, nutrients, seasonings and flavors. Include the first.
  • carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose, loli sugar and the like; And sugars such as polysaccharides such as conventional sugars such as dextrins, cyclodextrins, and xyls, sorbitols, and erythrates.
  • flavoring agents natural flavoring agents (tauumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used.
  • natural flavoring agents tauumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)
  • synthetic flavoring agents sacharin, aspartame, etc.
  • composition of the present invention may be provided in a pharmaceutical composition.
  • the composition of the present invention contains not only mate extract as an active ingredient, but also a pharmaceutically acceptable carrier.
  • Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are those commonly used in the preparation of lactose, dextrose, sucrose, sorbbi, manny, starch, acacia rubber, phosphate chalc, alginate, Gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyridone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil Including, but not limited to.
  • compositions of the present invention may be prepared in unit dosage form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporation into a multi-dose container.
  • the formulation may be in the form of a solution, suspension, or emulsion in an oil or an aqueous medium, or may be in the form of axes, powders, granules, tablets, or accelerators, and may further include a dispersant or stabilizer.
  • the present invention provides a method for evaluating the efficacy of pain relief, prevention or treatment of a sample comprising the following steps:
  • the sample to be analyzed is administered and the number or duration of ultrasound generation of 22-27 kHz generated from the animal to which the sample is administered is measured.
  • the frequency or duration of the 22-27 kHz lunar zone generated from the animal was measured and compared to the animal that did not receive the sample by measuring the frequency or duration of the ultrasonic
  • the sample is considered to be a substance for alleviating or treating pain.
  • the sample may be administered orally or parenterally, and in the case of parenteral administration, it may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like.
  • the sample used in the present invention is a peptide, an antibody, a peptide aptamer, AdNectin, affibody, US Patent No. 5,831,012, Avimer (Avimer, Silverman) , J. et al, Nature Biotechnology 23 (12): 1556 (2005)) or Kunitz domain, Arnoux B et al., Acta Crystal logr.D Biol.Crystal logr. 58 (Pt 7): 1252- 4 (2002)), and Nixon, AE, Current opinion in drug discovery & development 9 (2): 261-8 (2006).
  • Pain induction in animals in the present invention can be induced through drug administration, skin incision or nerve ligation. Pain-induced animals can use the pain animal model proposed by various pain-inducing methods known in the art.
  • the pain animal model used in the present invention may include a CCKChronic constriction injury model, a PSL / partial sciatic nerve ligation model, a spinal nerve ligation model, a split nerve injury model, a Vincrist in Vincrist in —Induced neuropathy model, Incision model, intradural catheterization model, direct lumbar puncture model.
  • the animal used in the evaluation method of the present invention is a rodent animal.
  • the animal used in the evaluation method of the present invention is a mouse (Mus musculus) or a rat (Rattus norvegicus). '
  • spontaneous pain is used to refer to pain that occurs in bones, joints, muscles, skin or connective tissue. This type of pain is typically very local.
  • “superficial pain” refers to pain felt along the skin segment where the nerves of the dorsal root are distributed, and is a direct pain that feels pain at the point of stimulation.
  • procedural pain refers to pain that occurs in a medical, dental or surgical procedure, which procedure is usually scheduled or associated with acute trauma.
  • Patient means any animal.
  • the patient is a human.
  • Other animals that can be treated using the compositions of the invention include non-human primates (eg, monkeys, gorillas, chimpanzees), livestock (eg, horses, pigs, goats, rabbits, sheep, cattle, llamas), and companion dogs. Animals, such as, but not limited to, guinea pigs, rats, mice, lizards, snakes, dogs, cats, ornamental fish, hamsters, and birds.
  • Nociceptive pain occurs in response to the activation of nociceptors by specific subsets of peripheral sensory neurons, i.e. intense or noxious stimuli.
  • Nociceptive pain generally provides a biological function of protection by acting as a warning of sensitive, self-limiting and potential or ongoing tissue damage.
  • Nociceptive pain is typically very limited locally. Examples of nociceptive pain include traumatic or surgical pain, labor pain, sprains, bone fractures, burns, bumps, bruises ( bruises, injections, dental procedures, skin biopsies, and obstructions.
  • Inflammatory pain may be associated with joints such as postoperative, post-traumat ic pain, arthritis (rheumatoid or osteoarthritis) pain, and axial low back pain. pain that occurs when there is tissue damage or inflammation, including pain associated with damage to joints, muscles, and tendons.
  • Neuropathic pain is often defined as chronic al lodynia (defined as pain due to irritation that usually does not cause pain, such as a light touch) and hyperalgesia (high sensitivity to normal pain stimulation). And may last for months or years after apparent healing of any damaged tissue. ⁇ effect ⁇
  • composition of the present invention not only has a palliative and therapeutic effect on the previously generated pain, but also has an effect of preventing pain when administered to a subject before the pain occurs.
  • the present invention provides a method for evaluating the efficacy of pain relief, prevention or treatment of a sample.
  • Figure 3 is an oral administration of mate extract to the experimental animals, and then performed the skin incision 6 hours after the experiment This is a measure of the number of times an animal generates ultrasound at the 22–27 kHz lunar calendar.
  • Figure 4 is an oral administration of mate extract to the experimental animals, the skin incision surgery 24 hours after the experiment This is the result of measuring the number of times an animal generates ultrasonic waves in the 22-27 kHz lunar calendar.
  • FIG. 7 is a diagram showing the manufacturing process of the skin incision model (acute pain model).
  • FIG. 8 is a diagram of a method for producing a nerve branch ligation injury model (chronic pain model).
  • 9 is a diagram showing the manufacturing process of the nerve branch ligation injury model.
  • 10 is a diagram showing a mechanical allodynia evaluation method.
  • 11 is a diagram illustrating a method for measuring ultrasonic utterance sound.
  • 12 is a diagram illustrating a result of ultrasonic sound measurement.
  • Figure 13 is a result of measuring the pain sensitivity of the surgical site by mechanical allodynia after 5 hours after intraperitoneal injection of gabapentin to the experimental animals immediately after the skin incision surgery.
  • FIG. 21 is a result of intraperitoneal injection of gabapentin into an experimental animal for 14 days after nerve branch ligation injury surgery, and then the pain sensitivity was measured by mechanical allodynia evaluation.
  • 25 shows the results of intraperitoneal injection of gabapentin into the experimental animals for 7 days after nerve branch ligation injury surgery, and then the number of times the experimental animals generate ultrasound at 22 kHz 27 kHz lunar zone.
  • FIG. 26 is a result of measuring the number of times the experimental animals generate ultrasound in the 22-27 kHz lunar zone after intraperitoneal injection of naproxen into the experimental animals for 7 days after nerve branch ligation injury surgery.
  • Natural product extract sample was purchased from Yaksudang (Korea) in Gyeongdong market as a raw material, and extracted by cutting before extraction. 70 vol% alcohol was added 10 times per 100 g of Mate raw material and extracted at 80 ° C. for 4 hours, and the filtrate and the residue extracts were combined, filtered and concentrated under reduced pressure. All extracts were filtered and concentrated under reduced pressure, lyophilized, and powdered and used in the experiment.
  • Spra ague-Daw ley (SD) rats (200-250 g, Male) were distributed in Samtako Co., Ltd. and used for experiments after being dropped in a breeding box for experimental animals for one week. Animals were kept under conditions of temperature 22 ⁇ rc, humidity 55 ° C 5%, day and night cycle (12 hours day / 12 hours night), and roughness of 300 Lux. Feed and water were freely fed. All animals were managed according to the Guidelines for the Use of Laboratory Animals by KFRI-IACUC (Korea Food Research Institute, Institutional Animal Care and Use Committee).
  • Body weights were measured and animals were randomly determined after adaptation, and individual identification of experimental animals was carried out using the skin pigmentation method.
  • Mate 70% alcohol extract samples were prepared by dissolving and suspending at a suitable concentration in distilled water. The prepared sample is operated
  • Gabapentin and naproxen were prepared by dissolving in saline (0.9% NaCl) at an appropriate concentration.
  • the prepared sample was intraperitoneal injection at a dose of 30 mg / kg / 3 ml immediately after surgery.
  • the same amount of saline was injected intraperitoneally immediately after surgery.
  • SNI Spared nerve injury
  • Neural branch ligation injury animal models have been proposed by Decosterd and Wool f (Decosterd & Woolf, 2000).
  • SD male rats (20 g 250 g) were used for general anesthesia using pentobarpital. After the rats under general anesthesia, left side view of the skin side of the thigh, and the incision and remove the gluteal daetoeyi (biceps femoris) were exposed to the three terminal branches of the sciatic nerve.
  • the sciatic nerve consists of three strands of nerves: the nasal nerve, the common peroneal never, and the tibial nerve.
  • the double gastrocnemius should remain intact without damage, branching to the right when observed from the left leg reference, the smallest nerve.
  • the total nasal bones and tibias are branched along the muscles in the direction of the legs, and then separated separately, firmly ligated using nylon 4-0 sutures, and then using forceps and scissors. 2-4 mm length was cut off and removed. After the nerve cutting was finished, the muscle layer was sutured, and then the skin incision was resealed and the experimental animals were transferred to a breeding cage for recovery. 5. Evaluation method
  • a method for measuring the degree of mechanical allodynia after animal pain modeling was described by Chaplan et al. (Chaplan et. Al, .1994).
  • the rats were placed in an acrylic triangle placed on a wire mesh test bench with a 2X2 mm mesh size and decanted for at least 15 minutes.When the rat movement became quiet, the pain threshold was measured using a continuous thickness of bone filament (Stoelting, USA). ) Values were evaluated.
  • the filament is placed vertically in contact with the left affected plantar foot and held for 5 to 6 seconds to indicate that the rat exhibits rapid evacuation reactions, or if it immediately flits or licks the plantar foot while releasing hairs.
  • Rats generate ultrasound when they are in pain, pain, atrophy, or stress, the range of which is reported to be 22-27 KHz (Portfors, 2007). Ultrasound produced by rats when they feel pain using USV measurement system (Sonot rack®, ver 1.5.0, Metris, Netherlands) for 10 minutes to measure the pain level for 3.5 hours, 6 hours and 24 hours after surgery (22—27 KHz) The sound was measured. The rats were placed in an acrylic box capable of measuring ultrasonic waves, stabilized for 15 minutes, and then subjected to ultrasonic measurement experiments for 10 minutes.
  • the pain relief effect of mate was measured by quantifying the number of ultrasound lunar zones (22–27 kHz) caused by the animals when they felt pain for 3.5 hours, 6 hours, 24 hours (P0D1) after skin incision. It was confirmed. After 6 hours, the 300 mg / kg group recorded 5.1 ⁇ 1.233 (calls), which was significantly decreased ( ⁇ .05), compared to 10.4 ⁇ 1.869 (calls). (FIG. 3). On day 1 postoperatively (P0D1), the control group had 14.0 ⁇ 3.296 (calls) in the ultrasound vocal measurements, while the 300 mg / kg group recorded 6.429 ⁇ 1.343 (calls) and significantly decreased (p ⁇ 0.05). It was confirmed (Fig. 4). Confirmation of Mate's Mass Mitigation Effect by Mechanical Allodynia Evaluation
  • the withdrawal threshold (g) value of the control group was 0.141 ⁇ 0.049 (g), whereas the positive control Gabapentin 30 mg / kg group had 7.486 ⁇ 1.308 (g). ⁇ .001) was confirmed to increase (Fig. 13).
  • the pain threshold (g) value of the control group was 0.087 ⁇ 0.027 (g) after 1 day after surgery (P0D1). It was confirmed that the size of significantly increased (p ⁇ 0.05) (FIG. 14).
  • control group 19.286 ⁇ 5.432 (calls), positive control group naproxen 30 mg / kg group 5.667 ⁇ 1.382 (calls) (* p ⁇ 0.05), 24 hours after surgery control group 24.143 ⁇ 6.967 (calls) positive control group naproxen 30 3.833 ⁇ 1.195 (calls) ⁇ ⁇ 0 ⁇ 05) was recorded in the mg / kg group, and it was confirmed that the decrease was significant ( ⁇ ⁇ 0.05).
  • the 22-27 kHz ultrasound recordings of the naproxen 30 mg / kg group decreased compared to the control group (FIG. 20).
  • the present inventors (Ilex paraguayensis) extract is a pain animal model skin In both the incision model and the nerve branch ligation injury model, the pain relief effect was confirmed. Especially, the short-term and long-term effects were confirmed. Therefore, using the composition containing the mate extract of the present invention as an active ingredient exhibits the effect of preventing or relieving pain.
  • the present invention is a short-term skin incision model and a long-term model
  • the ultrasonic sound measurement method is an excellent experimental method for the severity and quantification of pain.
  • the prevention and treatment of pain it is possible to minimize and overcome errors in individual differences and subjective judgments of the experimenter, which are disadvantages when the evaluation of mechanical allodynia alone is performed as an experimental method for determining the presence and extent of pain. I claim to be able to.

Abstract

La présente invention concerne une composition pour soulager, prévenir ou traiter la douleur contenant un extrait de maté comme principe actif. La composition de la présente invention a des effets de soulagement et de traitement de la douleur qui est survenue et affiche un effet de prévention de la douleur lorsqu'elle est administrée à un sujet avant que la douleur ne survienne. La composition de la présente invention affiche un effet de soulagement de la douleur remarquable, même par une administration par voie orale ainsi que par une injection intraveineuse, une application sur la peau ou analogue. La composition de la présente invention présentant ces caractéristiques est hautement applicable à un aliment. La présente invention concerne un procédé pour évaluer l'efficacité de soulagement, de prévention ou de traitement de la douleur d'un échantillon. L'utilisation de la présente invention permet de mesurer avec précision le nombre d'occurrences ou la durée de la vocalisation ultrasonique générée par animal expérimental en réponse à la douleur et d'exprimer les résultats de la mesure sous forme de valeurs numériques objectives, de telle sorte que la présente invention est très utile dans l'évaluation de l'efficacité du soulagement, de la prévention et du traitement de la douleur de l'échantillon et peut réduire au minimum les erreurs de l'état antérieur de la technique provenant de différences individuelles parmi les expérimentateurs et de jugements subjectifs dans la mesure de la réponse à la douleur.
PCT/KR2013/008702 2013-04-23 2013-09-27 Composition pour soulager, prévenir ou traiter la douleur contenant de l'extrait de maté comme principe actif et procédé pour évaluer l'efficacité du soulagement, de la prévention ou du traitement de la douleur d'un échantillon WO2014175518A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR20130044944A KR101483990B1 (ko) 2013-04-23 2013-04-23 시료의 통증 완화, 예방 또는 치료 효능에 대한 평가방법
KR1020130044943A KR101500485B1 (ko) 2013-04-23 2013-04-23 마테 추출물을 유효성분으로 포함하는 통증의 완화, 예방 또는 치료용 조성물
KR10-2013-0044944 2013-04-23
KR10-2013-0044943 2013-04-23

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050142236A1 (en) * 2003-12-29 2005-06-30 Boehringer Ingelheim International Gmbh Composition comprising an aqueous extract of red vine leaves and a diuretic
US20070004647A1 (en) * 2005-05-20 2007-01-04 Jack Arbiser Proteasome inhibitors and uses thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050142236A1 (en) * 2003-12-29 2005-06-30 Boehringer Ingelheim International Gmbh Composition comprising an aqueous extract of red vine leaves and a diuretic
US20070004647A1 (en) * 2005-05-20 2007-01-04 Jack Arbiser Proteasome inhibitors and uses thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BARDIN, L. ET AL.: "Comparison of milnacipran, duloxetine and pregabalin in the formalin pain test and in a model of stress-induced ultrasonic vocalizations in rats", NEUROSCIENCE RESEARCH, vol. 66, 2010, pages 135 - 140 *
BORTOLUZZI, M. C. ET AL.: "Pain levels after third molar surgical removal: an evaluation of predictive variables", THE JOURNAL OF CONTEMPORARY DENTAL PRACTICE, vol. 12, no. 4, 2011, pages 239 - 244 *
KUREJOVA, M. ET AL.: "An improved behavioural assay demonstrates that ultrasound vocalizations constitute a reliable indicator of chronic cancer pain and neuropathic pain", MOLECULAR PAIN, vol. 6, no. 18, 2010 *
WILLIAMS, W. O. ET AL.: "Ultrasonic sound as an indicator of acute pain in laboratory mice", JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE, vol. 47, no. 1, 2008, pages 8 - 10 *

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