1. Introduction
Orofacial pain sensation is related to intraoral and extraoral structures of the head and face, which are innervated by trigeminal ganglion neurons (Lazarov, 2002). The orofacial formalin test, which involves the injection of formalin into the lips of rats, is a behavioral model for studying the physiology and modulation of trigeminal nociception (Luccarini, Childeric, A., Gaydier, Voisin, & Dallel, 2006). On the other hand, trigeminal and facial branches are both mixed cranial nerves that carry sensory and motor information about the face, including those of the whiskers, maxilla, mandible, and teeth (Hogan, vanderVaart, Perampaladas, Machado, Einarson, & Taddio, 2014). In particular, the ventral buccal nerve and marginal mandibular branches of the facial and mandibular branches of the trigeminal nerves exhibit a complicated branching pattern and form communications with each other (Cobo, Solé-Magdalena, Menéndez, de Vicente, & Vega, 2017; Dörfl, 1985; Hwang, Yang, & Song, 2015; König, Hans-Georg, & Bragulla, 2007). It has been shown that neurons in rat trigeminal subnucleus caudalis, a nucleus in the medulla, receive information about dental pain (Carstens, Kuenzler, N., & Handwerker, 1998), touch, and temperature from the ipsilateral face (Carstens et al., 1998; Klein, Carstens, & Carstens, 2011).
Pain is an unpleasant sensation that can arise from inflammatory, surgical, or anesthetic injections. Pharmacological and non-pharmacological methods are used to reduce pain (Arendt & Tessmer-Tuck, 2013; Pahlavan et al., 2013; Yazdkhasti & Pirak, 2016). Various anesthetic solutions, such as lidocaine, an amide anesthetic, are available to relieve the perception of clinical pain (Rosivack, Koenigsberg, & Maxwell, 1990; Vickers & Punnia‐Moorthy, 1992). The efficacy, safety, and pharmacokinetics of drugs have been studied in different animal models to improve the quality of the anesthetic blocking properties (McGowan Jr & Davis, 2008). The solubility of anesthetic agents may increase with increasing temperature (Courtney, Agrawal, & Revington, 1999; Powell, 1987). Patients who receive local anesthesia report that warmed lidocaine significantly reduces pain (Courtney et al., 1999; Hogan et al., 2011; Lundbom et al., 2017). Moreover, warm-up (Ganji, Shirvani, Rezaei-Abhari, & Danesh, 2013) and cool-down (Dörfl, 1985) of the painful area can reduce pain because sensory inputs to the spinal cord can inhibit the crossing of pain signals by “closing the gate” (Adams & Bianchi, 2008). However, none of the previous studies (Courtney et al., 1999; Hogan et al., 2011; Lundbom et al., 2017) has examined the effects of temperature on pain relief, particularly in the face area. The effect of lidocaine temperature on the reduction of visceral pain has been considered. Although visceral and physical pains have a similar mechanism for pain detection, the type of pain sensation a person experiences, the pain receptors, the pain transmission pathway, and the type of pain response are different. Therefore, the study of pain due to formalin injection in the face and hind legs is generally different from the mentioned studies (Cervero, 2009). By using the formalin test , present study investigates the effects of Lidocaine (Lid.) temperature on acute and chronic pain in the hind paw under controlled conditions of body temperature and room temperature. 
On the other hand, in electrophysiology studies, a reduction in neuronal firing is considered representative of a reduction in pain sensation (Carstens et al., 1998; Klein et al., 2011). The single-unit recording technique is an invasive approach that investigates the activity of neurons more applicable to humans. The effects of lidocaine temperature changes on the orofacial formalin test and neural activity of the ventral buccal nerve as models for studying the success rate of anesthesia in rats were also evaluated. This study may benefit clinicians, particularly dentists, because the results show that better pain control may be achieved during injection and surgery by increasing the temperature of the local anesthetic.

2. Materials and Methods
Study animals
Male Wistar rats weighing 250±25 g were used in this experiment. The animals were kept in standard housing conditions with a 12:12 h light/dark cycle. Food and water were provided ad libitum. All experimental procedures were performed under protocols approved by the Ethics Committee of the Research Council of Kerman University of Medical Sciences (IR.KMU.REC.1398.679) and the Institutional Animal Care and Use Committee.

Behavioral study
Formalin-induced hind paw test 
The formalin-induced hind paw test was performed in a plexiglass chamber (25×25×25 cm) with a controlled floor temperature of 22°C (room temperature [RT]) or 37°C (Body Temperature [BT]). A mirror was placed underneath at a 45° angle to allow an unimpeded view of the rats. The rats were randomly divided into five groups (n=7). Lidocaine (2%, 0.1 mL) (Perzocaine, DaruPakhsh, and Tehran, Iran) (Inan et al., 2009) was injected into their right hind legs to block sensation on the dorsal side of the hind paw. The control groups received Saline (Sal) in the same volume. In the RT-Sal and RT-Lid. groups, subjects received saline or lidocaine at room temperature (22°C). In the BT-Sal and BT-Lid. groups, subjects received the lidocaine at 37°C temperature. Also, during the experiment in these groups, the plexiglass floor temperature was fixed at 37°C using a heater. Saline or lidocaine was injected 10 min before intraplantar injection of formalin (50 µL of 5% v/v) into the right hind-paw (Dubuisson & Dennis, 1977). The control rats only experienced an intraplantar injection of formalin. The animal was immediately returned to the plexiglass chamber. Animals were observed from the start to 5 min (acute phase) and then from 15 to 60 min (chronic phase). The total time spent licking and biting the injected paw was recorded and considered indicative of nociception (Dubuisson & Dennis, 1977). 

Orofacial formalin test
The orofacial formalin test was performed according to a previous study (Patel et al., 2013). Rats were randomly divided into five groups, as mentioned above (n=7). In the BT-Sal, RT-Sal, BT-Lid., and RT-Lid. groups, the subjects were injected in the lower right lip with saline (0.1 mL) or 2% lidocaine (0.1 mL) (Perzocaine, DaruPakhsh, and Tehran, Iran) (Inan et al., 2009) using a 30-gauge needle fitted to a 50 µL Hamilton syringe. Ten minutes later, the animals received a subcutaneous injection of formalin (25 µL, 2%v/v) in the lower right lip (Patel et al., 2013). The control rats only received a subcutaneous injection of formalin. Each rat was placed in a clear plastic box (25×25×25 cm) with a mirror underneath at a 45° angle to create an unimpeded view of the rats. The number of rubbings of the lip was recorded from 0 to 5 min (acute phase) and then from 15 to 60 min (chronic phase). The results were considered indicators of nociception (Patel et al., 2013). 

Electrophysiology study 
In the electrophysiological study, 21 animals were randomly divided into two groups. Here, in the RT group (n=10), lidocaine 2% was injected at room temperature with a volume of 0.07 mL, while in the BT group (n=11), the temperature of lidocaine was 37°C. An insulin syringe plunger (Dena, Karachi, Pakistan) and 27-gauge short needles (Sofijet, Mazamet, France) were used for intradermal injection after nerve exposure.

Electrophysiology procedure
Recording
The rats were anesthetized by an intraperitoneal injection of urethane anesthetic (1.2 g/kg), and then the animals were fixed by the stereotactic frame in the supine position. The ventral buccal (marginal) nerve was exposed after making an incision in the mandibular skin (Heaton et al., 2014). For the single-unit recording technique, a single metal electrode was inserted into the marginal nerve by a micro driver (WPI, USA). An E-Lab device (Parto Danesh, Iran) was utilized to record the activity of neurons. Then 10 min of the spontaneous activity of the marginal nerve was recorded, ensuring that the base activity of the neuron remained stable. Then the anesthetic solution was injected by the intradermal cheek method (the injection area was in the animal’s rostrum, 1 cm from the exposed nerve). The activities of the single neurons were recorded for 60 min (Figure 3).

A homoeothermic blanket control unit (Harvard, Holliston, USA) was used to reduce heat exchange; it was set to 37°C by putting the heat sensor inside the animal’s anus. At the end of the procedure, the animals were sacrificed via deep anesthesia with CO2 (Herfst & Brecht, 2008; Hohman, Kleiss, Knox, Weinberg, Heaton, & Hadlock, 2014).

Statistical analysis 
Using a post-stimulus time histogram (PSTH), the neural activities of the marginal nerve were recorded at intervals of 0–3000 s (Figure 3). Then, the number of spikes per equal bin (bin=250 s) was calculated as the response of neurons. After the Kolmogorov-Smirnov normality test, one-way ANOVA and two-way ANOVA followed by Bonferroni post hoc tests were used to compare the total time spent licking, the total number of rubbing the lip, and the number of spikes per bin. The data were presented as Mean±SEM, and P<0.05 was considered statistically significant.

3. Results 
Effects of lidocaine at different temperatures on formalin-induced hind paw pain
The one-way ANOVA test followed by the Bonferroni test showed a statistically significant difference in the total time spent licking the hind paw among the treatment groups in both acute (F4, 30=183.3, P<0.001) and chronic (F4, 30=210.3, P<0.001) phases. ANOVA results showed no statistically significant difference among the control, RT-Sal, and BT-sal groups in acute or chronic phases.
Figure 1 shows that total time spent licking the hind paw decreased significantly in both RT-Lid. and BT-Lid. groups compared to control groups (P<0.001) during acute and chronic phases.

Moreover, in the acute phase, lidocaine had significant antinociceptive effects in the RT-Lid. group (81.6%) and the BT-Lid. group (98.7%) compared to the control groups (P<0.05). Also, in the chronic phase, lidocaine had significant antinociceptive effects in the RT-Lid. group (72.4%) and the BT-Lid. group (93.2%) compared to the control groups (P<0.05). 

Effects of lidocaine at different temperatures on formalin-induced orofacial pain
One-way ANOVA followed by the Bonferroni test showed a significant difference in the number of rubbings among treatment groups in the acute (F4, 30=122.0, P<0.001) and chronic (F4, 30=84.8, P<0.001) phases. At room or body temperature, the saline groups did not indicate any statistical significance in the number of rubbings compared to the control group in both acute and chronic phases. Further analyses showed that the BT-Lid. and RT-Lid. groups had a significant reduction in the number of lip rubbings as compared to the control groups (P<0.001) during acute and chronic phases of the orofacial pain model (Figure 2).

However, there is no significant statistical difference between RT-Lid. and BT-Lid. groups, but lidocaine decreased the number of rubbings in the RT-Lid. (88.2%) and the BT-Lid. (97.3%) groups compared to the control group in the acute phase. In the chronic phase, lidocaine at room and body temperatures had an antinociceptive effect on the RT-Lid. (83.8%) and BT-Lid. (91.7%) groups compared to the control groups, respectively.

Effects of lidocaine at different temperatures on firing rate of the ventral buccal nerve
One-way analysis followed by the Bonferroni test showed a significant difference in the spontaneous activity of neurons (F3, 40=11.01, P=0.001) following treatment with lidocaine at different temperatures. As shown in Figure 4A, the neurons’ baseline activity did not significantly differ between the BT-Lid. and the RT-Lid. groups. The results revealed that following lidocaine injections at different temperatures, the number of spikes per bin decreased significantly in both the BT-Lid. and RT-Lid. groups compared to their baseline activities (P<0.05, and P<0.001, respectively). Although there was no difference between lidocaine treatments on the number of spikes compared to their baselines, lidocaine at room and body temperature had an inhibitory effect (about 50.3% and 64.9%, respectively) on the number of spikes.

Further analysis by two-way ANOVA followed by Bonferroni test on the number of spikes per bin indicate that the main effect for treatment (F1, 247=3.89, P=0.04) and time (F12, 247=4.3, P=0.001) were revealed but not for the interaction of treatment * time (F12, 247=0.037, P=0.99). The results indicate that the number of spikes per bin decreased significantly in the BT-Lid. group compared to the baseline at 0–3000 s after lidocaine injection (P<0.01), while a significant reduction in the number of spikes per bin was observed at 0–1000, 1250–2250, and 2750–3000 s in the RT-Lid. group compared to its baseline (P<0.05) (Figure 4B).

4. Discussion
In the present study, the anesthesia success rate was investigated at different temperatures of lidocaine administration. Behavioral and electrophysiological data showed that lidocaine acts better at BT than at RT in reducing formalin-induced pain and the neural activity of the marginal nerve. In formalin-induced hind paw pain, rats were placed in a box with a floor temperature of 37°C for 10 min, and they were treated with lidocaine at BT. Therefore, heat could decrease the pain by the gate theory mechanism in the spinal cord (Ropero Peláez & Taniguchi, 2016). The pain threshold increases as the temperature rises, and also heat can affect metabolism, blood circulation, and muscle spasms (Frölich et al., 2016). In line with the present study, Lundbom et al. showed that after subcutaneous injection of lidocaine into the abdominal cavity of 36 participants, of 9 patients preferred injection at refrigerated temperature, 9 patients endorsed lidocaine at ambient temperature, and the others had less pain with heated lidocaine to 38oC (Lundbom et al., 2017). Moreover, in a meta-analysis in 2011, Hogan et al. reviewed 29 papers and found that warming local anesthetics can reduce pain in intradermal and subcutaneous injections. However, they concluded that the efficacy of warming anesthetic solutions for intraoral injections was not significant (Hogan et al., 2011). The present study showed lidocaine is more effective at BT than at RT in the acute and chronic phases of formalin-induced orofacial pain. Previous studies showed that the acute phase is related to the activation of peripheral nociceptors, while the chronic phase of the formalin test involves the continuous activity of primary afferents and increases the sensitivity of dorsal horn neurons (Murray, Porreca, & Cowan, 1988; Taylor, Peterson, & Basbaum, 1995). Moreover, intrathecal lidocaine pretreatment before formalin injection in rats decreases c-Fos expression on the dorsal horn of the spinal cord (Inan et al., 2009). 
In rodents and humans, trigeminal and facial nerve branches are mixed with cranial nerves that carry sensory information from teeth to the brain (Cobo et al., 2017; Dörfl, 1985; Hwang et al., 2015; König et al., 2007). Previous studies have illustrated that the wide range of neurons from the trigeminal nerve nuclei increases their activity in response to peripheral stimuli, including those from rats’ dental pulp (Hamba, Hisamitsu, & Muro, 1992; Roch, Messlinger, Kulchitsky, Tichonovich, Azev, & Koulchitsky). The root of the incisor in rats has a wide-open shape; therefore, a dental pulp electrical stimulation may spread out beyond the tooth pulp (Myslinski & Matthews, 1987). However, ferret canine teeth are more suitable for electrical or thermal stimulation (Ahn et al., 2012). The marginal nerve is more accessible than the cranial trigeminal subnucleus caudalis in rats; therefore, the marginal nerve was exposed to record in vivo neural activity in the present study.
According to the electrophysiology data of the present study, the use of anesthesia at 22°C and 37°C significantly reduced neuron spikes compared to baselines after the injection of 2% lidocaine and the warmer lidocaine was more effective than the others. As mentioned, lidocaine solubility increases with rising temperature (Powell, 1987), and this can be one of the reasons why the solution acts faster when the temperature rises and leads to faster induction of anesthesia. The function of local anesthetics is to block changes in the diffusion of the nerve impulses along the nociceptor by inhibiting sodium channels (Hwang et al., 2015). Moreover, warming the anesthetic agent to body temperature may assist the molecule in infiltrating the nociceptor, consequently contributing to faster blocking of the sodium channels, thereby preventing pain signals by increasing the fluidity of the lipid membrane. Also, lidocaine could cross the nerve membrane more comfortably, achieving effective concentration to produce analgesia more instantaneously (Caterina, Schumacher, Tominaga, Rosen, Levine, & Julius, 1997).
Finally, successful anesthesia has been described as the lack of response of a volunteer who has received anesthesia to coldness or two consecutive maximum output electric pulp sensibility tests (Sampaio, Carnaval, T. G., Lanfredi, Horliana, Rocha, & Tortamano, 2012). In dental medicine, the fear of pain attributed to anesthetic injection has been proven to be an obstacle to providing appropriate dental care (Armfield & Milgrom, 2011; Milgrom, Coldwell, Getz, Weinstein, & Ramsay, 1997). Although pain cannot be eliminated at the time of injection, it can be significantly relieved. It has been shown that less pain during the procedure accompanies a higher success rate of injection (Hargreaves & Keiser, 2002). According to the present data, increasing the temperature of lidocaine may optimize the success rate of anesthesia in dentistry. Similar to our report, some studies suggest that warming the anesthetic can reduce injection pain and increase anesthesia success. Pre-warming and buffering the anesthetic solution reduces pain during administration and procedures in maxillary and mandibular teeth (Kurien, Goswami, & Singh, 2018). Rogers et al. found that using anesthesia at 37°C was more comfortable than at room temperature (Rogers, Fielding, & Markiewicz, 1989). In contrast, other studies have suggested that warming the anesthetic does not affect pain. By studying 44 children, Ram, Hermida, & Peretz (2002) concluded that there was no significant difference between the pain experienced during the injection in the group injected with a cartridge at room temperature with a group that received the injection from a warmed cartridge (Ram et al., 2002).
A limitation of this study was that we selected the percentage of formalin based on previous studies (Dubuisson & Dennis, 1977; Inan et al., 2009; Patel et al., 2013). As there is a correlation between formalin concentration and the rubbing activity (Clavelou, Dallel, Orliaguet, Woda, & Raboisson, 1995), it is possible that the effects of temperature changes could have been more prominent if the percentage of formalin had been lower. In the electrophysiology phase of this study, only the effect of temperature differences in the absence of a pain stimulus was examined. These issues can be further explored in complementary studies in the future.

5. Conclusion
The present study showed that warming the lidocaine cartridges to 37°C increased anesthesia success compared to anesthesia-induced at room temperature. Accordingly, a warmed anesthetic cartridge could be used to control pain by increasing the success rate during dental injection and may also apply to clinical studies on humans. Moreover, the models designed in the present study can be used in other studies to compare with other anesthetic solutions or to test the anesthetic effect of materials.

Ethical Considerations
Compliance with ethical guidelines
The the Ethics Committee Research Council of Kerman University of Medical Sciences approved this study (IR.KMU.REC.1398.679).

Funding
The paper was extracted from the Ph.D. dissertation of the first author, Department of Oral and Dental Diseases Research Center, Dental School, Kerman University of Medical Sciences, Kerman, Iran.

Authors' contributions
Conceptualization and Supervision: Masoud Parirokh and Mohammadreza Afarinesh; Methodology: Vahid Sheibani and Mohammadreza Afarinesh; Investigation, Writing-original draft, and Writing-review & editing: All authors; Data collection: Sina Kakooei, Reza Nikzad, Mahshid Mostafavi, And Amir Nekouei; Data analysis: Mohammadreza Afarinesh and Mansoureh Sabzalizadeh.

Conflict of interest
The authors declared no conflict of interest.

Acknowledgments
The authors would like to thank the staff of Kerman Neuroscience Research Center in conducting the study.


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