CN115969317A - Thermal stimulation pain testing device and testing method - Google Patents
Thermal stimulation pain testing device and testing method Download PDFInfo
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- CN115969317A CN115969317A CN202211590248.9A CN202211590248A CN115969317A CN 115969317 A CN115969317 A CN 115969317A CN 202211590248 A CN202211590248 A CN 202211590248A CN 115969317 A CN115969317 A CN 115969317A
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Abstract
The invention relates to the technical field of neuropathic pain of experimental non-human primates, and particularly discloses a thermal stimulation pain testing device and a testing method. Comprises a temperature control heating device and a continuous walking induction device; the temperature control heating device comprises a constant temperature timing heating module and a fixing band; the continuous walking induction device comprises a transparent limiting box, wherein the transparent limiting box consists of a front side plate, a left side plate, a right side plate, a top plate and a rear side plate; a transparent feeder is arranged on the front side of the front side plate; the front side plate is provided with a feeding port through which non-human primate experimental animals walking in the transparent limiting box are fed; the transparent limiting box is fixed right above a walking crawler of the treadmill. The invention has the advantages of realizing scientific, effective, accurate, controllable and objective heat stimulation pain test, meeting the drug effect detection of new drugs for neuropathic pain, and the like.
Description
Technical Field
The invention relates to the technical field of neuropathic pain of experimental animals of nonhuman primates, in particular to a thermal stimulation pain testing device and a testing method.
Background
Pain is the most common symptom of various diseases and is one of the most serious problems afflicting human health today. The types of analgesics clinically applied at present are limited, and most of the analgesics have the obvious side effects of weak analgesic effect and/or addiction, tolerance and the like, so that a large number of pain patients cannot be effectively treated. Therefore, various pharmaceutical factories or drug research and development institutions are developing novel analgesics with no addiction and little side effect. However, since it is difficult to directly perform pain and drug effect tests on human body after the development of new drugs, it is often important to screen and identify candidate analgesic drugs or detect the drug effect and side effects of new drugs by establishing pain animal models, especially to model pain diseases and test new drugs with non-human primate experimental animals. Firstly, the first step is the modeling of pain diseases, and secondly, the testing of the drug effect of new drugs is carried out. The research on the modeling of pain diseases is still less, in particular, the modeling of pain diseases of non-human primate experimental animals has no deep research and feasible scheme, no effective animal disease model exists, and the test of new drugs cannot be mentioned. Meanwhile, in the pain test process, because the non-human primate experimental animal cannot communicate with people, how to objectively and intuitively evaluate indexes such as pain indexes in the related test process is also a great technical problem in the pain test of the non-human primate experimental animal at present. Thus, pain testing and methods are still lacking at present. The technical problems cannot be effectively solved, and related new pain medicines cannot be effectively tested on non-human primate experimental animals directly, so that evaluation and test of new pain medicines are seriously hindered.
Disclosure of Invention
The invention provides a thermal stimulation pain testing device and a testing method with good reliability aiming at the technical problems.
In order to achieve the purpose, the invention adopts the following technical scheme:
the heat stimulation pain testing device comprises a temperature control heating device and a continuous walking induction device; the temperature control heating device comprises a constant temperature timing heating module and a fixing band; the continuous walking induction device comprises a transparent limiting box, wherein the transparent limiting box consists of a front side plate, a left side plate, a right side plate, a top plate and a rear side plate; a transparent feeder is arranged on the front side of the front side plate; the front side plate is provided with a feeding port through which non-human primate experimental animals walking in the transparent limiting box are fed; the transparent limiting box is fixed right above a walking crawler of the treadmill.
Preferably, the transparent limiting box is also provided with a plurality of air holes at the front upper part.
Preferably, a fan is further disposed at the front upper portion of the transparent limiting box, and the fan is disposed at the outer side of the ventilation hole.
Preferably, the transparent food feeder comprises a transparent food storage chamber, the lower part of the transparent food storage chamber is provided with a food falling port, and the food falling port is provided with a valve; the lower end of the food falling opening is provided with a dragging type food feeding box; the dragging type food feeding box can be movably arranged at the food feeding opening.
Preferably, the transparent feeder further comprises a feeding box supporting base, the feeding box supporting base is arranged below the dragging type feeding box, and a clamping device is correspondingly arranged between the feeding box supporting base and the dragging type feeding box.
The test method using the thermal stimulation pain test device as described above includes the steps of:
(1) Disease modeling
S1: injecting capsaicin: injecting capsaicin into inner thigh of experimental non-human primate 100 μ l/50 μ g intradermally;
s2: heating induction, namely applying the temperature-controlled heating device to an injection area for more than 38 ℃ and maintaining the temperature for more than 100s so as to prompt the experimental non-human primate to represent symptoms of neuropathic pain;
(2) Symptom characterization test using the thermal stimulation pain test device
Step 1: at the latest before starting the temperature control heating device for 100s after heating the non-human primate experimental animal, ensuring that the non-human primate experimental animal normally walks on a walking track of a running machine in the thermal stimulation pain testing device, starting timing after starting heating, and simultaneously recording videos of the non-human primate experimental animal;
step 2: and stopping timing when the leg of the non-human primate experimental animal shows pain. Preferably, the temperature rise is induced by applying 43 ℃ to the injection region for 100 seconds or more by using the temperature-controlled heating device.
Preferably, the temperature rise induction is performed by a double-control temperature rise method, i.e., the injection region is subjected to the temperature control heating device for 38 ℃ and maintained for more than 15 seconds, and then subjected to the temperature control heating device for 43 ℃ and maintained for more than 120 seconds.
Preferably, when the effect of the new drug to be tested is tested, the drug administration of the new drug to be tested is completed before capsaicin is injected into the experimental non-human primate.
Preferably, the disease modeling and the symptom characterization test are performed 30min after the completion of the administration of the new drug to be tested and/or 60min after the completion of the administration of the new drug to be tested and/or 120min after the completion of the administration of the new drug to be tested, respectively.
Compared with the prior art, the invention has the beneficial effects that:
1. according to the thermal stimulation pain testing device, the continuous walking induction device is arranged to induce the non-human primate experimental animal disease model to show pain representation, so that the objectivity of pain testing evaluation is ensured, and the problem that effective objective evaluation cannot be realized in the non-human primate experimental animal pain testing all the time is solved; the invention also stimulates the experimental non-human primates to walk in continuous cooperation by adopting the transparent feeder, thereby ensuring that the pain characterization can be well reflected.
2. According to the invention, a scheme of capsaicin, a temperature-controlled heat applying device and a continuous walking inducing device is adopted to induce and detect a disease model, so that scientific, effective, accurate, controllable and objective thermal stimulation pain test can be realized, and the drug effect detection of a new drug for neuropathic pain can be met.
Drawings
FIG. 1 is a schematic structural view of a transparent feeder of the continuous travel inducing apparatus of the present invention in a closed state;
FIG. 2 is a schematic view showing the transparent feeder of the continuous travel induction apparatus according to the present invention in a feeding state;
FIG. 3 is a schematic view of the valve area of the transparent feeder of the present invention;
FIG. 4 is a cross-sectional view of the transparent feeder of the present invention;
FIG. 5 is a cross-sectional view of a temperature controlled heat application apparatus of the present invention;
FIG. 6 is the capsaicin-induced pain response latency time to heat stimulation in cynomolgus monkeys after oral administration of gabapentin in Table 2;
FIG. 7 is a graph of capsaicin-induced pain response latency to heat stimulation in cynomolgus monkeys, following oral administration of gabapentin drug to cynomolgus monkey 2 in Table 2;
FIG. 8 is a graph of capsaicin-induced pain response latency in cynomolgus monkeys after oral administration of gabapentin in Table 2;
FIG. 9 is a graph of the incubation time of capsaicin induced thermal stimulation pain response in cynomolgus monkeys after oral administration of gabapentin drug to cynomolgus monkey 4 in Table 2.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be obtained by a person skilled in the art without inventive step based on the embodiments of the present invention, are within the scope of protection of the present invention.
In the description of the present invention, it should be noted that the terms "inside", "front", "back", "left", "right", and the like indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings or orientations or positional relationships conventionally put in use of products of the present invention, and are only for convenience of description and simplicity of description, but do not indicate or imply that the referred devices or elements must have specific orientations, be constructed in specific orientations, and be operated, and thus, should not be construed as limiting the present invention.
In the description of the present invention, it should also be noted that, unless otherwise explicitly specified or limited, the terms "disposed" and "connected" are to be interpreted broadly, e.g., as being either fixedly connected, detachably connected, or integrally connected; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The specific meanings of the above terms in the present invention can be understood in specific cases to those skilled in the art.
As shown in fig. 1 to 5, the thermal stimulation pain test device includes a temperature-controlled heat applying device and a continuous walking inducing device; the temperature control heating device comprises a constant temperature timing heating module 23 and a fixing band 26; in this embodiment, the constant temperature timing heating module 23 includes a heating metal plate 25 and a control circuit 24, and may further be integrated with a power supply and a start switch, and when in use, the heating mode and the constant temperature time are stored in the chip, and the heating is stopped after the constant temperature time is reached, so as to meet the test requirement and not to damage animals.
The continuous walking induction device comprises a transparent limiting box, wherein the transparent limiting box consists of a front side plate 10, a left side plate, a right side plate 13, a top plate 12 and a rear side plate 14; the front side of the front side plate 10 is provided with a transparent feeder 7; the front side plate 10 is provided with a feeding port 10-1, and the non-human primate experimental animals walking in the transparent limited box are fed through the feeding port 10-1; the transparent confinement box is fixed directly above the walking track 1 of the treadmill. When the induction type walking machine is used, the non-human primate experimental animals are induced to continuously cooperate with the walking crawler 1 of the running machine to walk by taking food as a reward product, namely: clamping the transparent limiting box onto the machine bodies on two sides of a walking crawler 1 of the running machine through a fixing block 2 at the bottom through a U-shaped clamp, then placing the non-human primate experimental animals into the transparent limiting box, then placing food into the transparent limiting box, and performing long-term training on the non-human primate experimental animals before testing, namely prompting the non-human primate experimental animals to be willing to cooperate with continuous walking for a certain time, stopping the running machine and immediately giving reward food from the food feeding port 10-1, and if the non-cooperation walking or the continuous walking is not up to the requirement, not giving the reward food; after long-term training, the conditioned reflex of the experimental non-human primates can be induced, and then relevant tests can be carried out. According to the invention, the reward food is placed in the transparent feeder 7, so that the non-human primate experimental animals can see the reward food in time, the matching degree of the non-human primate experimental animals is further improved, and the whole process of completing the pain test by matching the non-human primate experimental animals can be effectively ensured.
Preferably, the transparent box for limiting the animal temperature is characterized in that a plurality of air holes 11 are further formed in the front upper portion of the transparent box for limiting the animal temperature, a fan 8 is further arranged on the outer side of the air holes 9 of the front side plate 10, and certainly, the fan can be installed on the outer side of the air holes 11, so that air can be blown in from the front upper portion through the fan 8 when the transparent box for limiting the animal temperature is used, air can be discharged from the lower portion of the transparent box for limiting (a gap is formed between the bottom of the transparent box for limiting the animal temperature and the walking crawler 1), the stuffiness of the experimental non-human primates in the transparent box for limiting the animal temperature can be reduced, the peculiar smell of the experimental non-human primates can be reduced, the comfort of the experimental non-human primates can be improved, and the matching degree of the experimental non-human primates can be further improved. In this embodiment, the rear side plate 14 is connected to the left and right side plates 13 in a manner of pulling up and down, and the purpose of the design is as follows: the rear side plate 14 is used as a sliding door, so that the non-human primate experimental animals can conveniently enter and exit.
Preferably, the transparent food feeder 7 comprises a transparent food storage chamber, the lower part of the transparent food storage chamber is provided with a food falling port 16, and the position of the food falling port 16 is provided with a valve 6; the lower end of the food falling opening 16 is provided with a dragging type food feeding box 5; the dragging type food feeding box 5 can be movably arranged at the food feeding opening 10-1. In this embodiment, as shown in fig. 3, the bottom surface of the transparent food storage chamber is designed to be inclined, then the valve 6 is of a pull-out type, an opening 18 is formed in the middle of the valve 6, then a valve insertion opening 17 is formed in the position of the food falling opening 16 corresponding to the pull-out type valve 6, and when the food storage chamber is used, the valve 6 is pushed and pulled, so that food is further forced to fall from the opening 18, and the falling of the food is controlled.
Preferably, the transparent feeder further comprises a feed box supporting base 3, the feed box supporting base 3 is arranged below the dragging type feed box 5, a locking device is correspondingly arranged between the feed box supporting base 3 and the dragging type feed box 5, the locking device in the embodiment can select a spring plunger 4, and then a plunger locking hole 21 is correspondingly arranged on the bottom surface 20 of the dragging type feed box 5, and the function of the transparent feeder is mainly to realize the self-locking function of the dragging type feed box 5. When the food storage box is used, food in the transparent food storage chamber is firstly dropped into the food taking groove 22 of the dragging type food feeding box 5 in the state of figure 1, then when reward food needs to be given to the non-human primate experimental animal, the food is pushed inwards by holding the handle 19 of the dragging type food feeding box 5, the plunger clamping hole 21 is promoted to be separated from the spring plunger 4, then the food taking groove 22 is pushed into the state of figure 2, the non-human primate experimental animal can grab the reward food at this time, the conditioned reflex is established, and the continuous matching degree of the non-human primate experimental animal is improved.
The test method using the thermal stimulation pain test device as described above includes the steps of:
(1) Disease modeling
S1: injecting capsaicin: injecting capsaicin into inner thigh of experimental non-human primate 100 μ l/50 μ g intradermally;
s2: heating induction, namely applying the temperature-controlled heating device to an injection area for more than 38 ℃ and maintaining the temperature for more than 100s so as to prompt the experimental non-human primate to represent symptoms of neuropathic pain;
(2) Symptom characterization test using the thermal stimulation pain test device
Step 1: at the latest before starting the temperature control heating device for 100s after heating the non-human primate experimental animal, ensuring that the non-human primate experimental animal normally walks on a walking track of a running machine in the thermal stimulation pain testing device, starting timing after starting heating, and simultaneously recording videos of the non-human primate experimental animal;
step 2: and stopping timing when the leg of the non-human primate experimental animal has pain characteristics. Preferably, the temperature rise is induced by applying 43 ℃ to the injection region for 100 seconds or more by using the temperature-controlled heating device.
Preferably, the temperature rise induction is performed by a double-control temperature rise method, i.e., the injection region is subjected to the temperature control heating device for 38 ℃ and maintained for more than 15 seconds, and then subjected to the temperature control heating device for 43 ℃ and maintained for more than 120 seconds.
Preferably, when the effect of the new drug to be tested is tested, the administration of the new drug to be tested is completed before capsaicin is injected into the experimental non-human primate.
Preferably, the disease modeling and the symptom characterization test are performed 30min after the completion of the administration of the new drug to be tested and/or 60min after the completion of the administration of the new drug to be tested and/or 120min after the completion of the administration of the new drug to be tested, respectively.
The specific test process is as follows:
study of latency of pain response to thermal stimulation
The pain model of the cynomolgus monkey is induced by capsaicin, and the latency time of the pain reaction of the cynomolgus monkey is detected by thermal stimulation.
1. Establishing a baseline
That is, in the susceptibility test of the non-human primate experimental animals to the thermal stimulus without capsaicin injection, the average response latency was 117.1s as shown in Table 1.
2. Study of latency to pain response to thermal stimulus
After capsaicin injection, the gradual sensitivity of non-human primate experimental animals to thermal stimulation is studied, and as shown in table 1, the average response latency time of 90 minutes is 14.9s at the shortest; then the latency was gradually increased to an average response latency of 105.6s for 8 hours.
TABLE 1 capsaicin induced incubation time for heat stimulated pain response in cynomolgus monkeys
Through the above experiments, it was found that: the cynomolgus monkey's response to hot stab pain is most sensitive 30 minutes to 4 hours after capsaicin injection, and then preferably 30 minutes, 60 minutes, 120 minutes after administration as the time of standard test.
(2) Simulated drug therapy testing
Gabapentin (Gabapentin) was the first therapeutic drug developed by Warner-Lanbert, usa and was currently recognized to show a significant effect in animal models of spasticity, analgesia, and amyotrophic lateral sclerosis. Therefore, in the experiment, a capsaicin-induced pain model of the cynomolgus monkey with better reaction stability is screened, and then the pain reaction latency time of the cynomolgus monkey is detected by thermal stimulation before and after the oral administration of the gabapentin drug (the drug is applied according to 30 mg/KG). As shown in Table 2, the average latency time to response to heat-stimulated pain in cynomolgus monkeys was 43s before capsaicin injection. Before administration (after capsaicin injection), the average latency time to response to heat-stimulated pain in cynomolgus monkeys was 12s. The mean response latency times were 83s, 37s, and 77s 30min, 60min, and 120min after administration, respectively.
TABLE 2 incubation time of capsaicin induced heat stimulated pain response in cynomolgus monkeys after oral administration of gabapentin drug
Claims (10)
1. The heat stimulation pain testing device is characterized in that: comprises a temperature control heating device and a continuous walking induction device; the temperature control heating device comprises a constant-temperature timing heating module and a fixing band; the continuous walking induction device comprises a transparent limiting box, wherein the transparent limiting box consists of a front side plate, a left side plate, a right side plate, a top plate and a rear side plate; a transparent feeder is arranged on the front side of the front side plate; the front side plate is provided with a feeding port through which non-human primate experimental animals walking in the transparent limiting box are fed; the transparent limiting box is fixed right above a walking crawler of the treadmill.
2. The thermally stimulated pain testing device of claim 1, wherein: the upper front part of the transparent limiting box is also provided with a plurality of air holes.
3. The thermally stimulated pain testing device of claim 2, wherein: the upper front part of the transparent limiting box is also provided with a fan, and the fan is arranged on the outer side of the air holes.
4. The thermally stimulated pain testing device of claim 1, wherein: the transparent food feeder comprises a transparent food storage chamber, the lower part of the transparent food storage chamber is provided with a food falling opening, and the food falling opening is provided with a valve; the lower end of the food falling opening is provided with a dragging type food feeding box; the dragging type food feeding box can be movably arranged at the food feeding opening.
5. The thermally stimulated pain testing device of claim 4, wherein: the transparent feeder also comprises a feeding box supporting base, the feeding box supporting base is arranged below the dragging type feeding box, and a clamping device is correspondingly arranged between the feeding box supporting base and the dragging type feeding box.
6. A test method using the thermal stimulation pain test apparatus according to any one of claims 1 to 5, characterized by comprising the steps of:
(1) Disease modeling
S1: injecting capsaicin: injecting capsaicin into inner thigh of experimental non-human primate 100 μ l/50 μ g intradermally;
s2: heating and inducing: applying the temperature-controlled heating device to the injection area at a temperature above 38 ℃ for more than 100s, thereby prompting the experimental non-human primates to represent symptoms of neuropathic pain;
(2) Symptom characterization test using the thermal stimulation pain test device
Step 1: at the latest before starting the temperature control heating device for 100s after heating the non-human primate experimental animal, ensuring that the non-human primate experimental animal normally walks on a walking track of a running machine in the thermal stimulation pain testing device, starting timing after starting heating, and simultaneously recording videos of the non-human primate experimental animal;
step 2: and stopping timing when the non-human primate experimental animal shows the pain characterization.
7. The test method of claim 6, wherein: the temperature rise induction is carried out by applying 43 ℃ for more than 100 seconds to an injection area by using the temperature-controlled heating device.
8. The test method of claim 6, wherein: the temperature rise induction adopts a double-control temperature rise mode, namely, the temperature of the injection area is firstly applied for 38 ℃ and maintained for more than 15s by using the temperature control heating device, and then the temperature is applied for 43 ℃ and maintained for more than 120 s.
9. The test method of claim 6, wherein: when the effect of the new drug to be tested is tested, the drug administration of the new drug to be tested is completed before capsaicin is injected into the experimental non-human primate.
10. The test method of claim 9, wherein: and respectively carrying out the disease modeling and the symptom characterization detection 30min after the administration of the new drug to be detected is completed, or/and 60min after the administration of the new drug to be detected is completed, or/and 120min after the administration of the new drug to be detected is completed.
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