In both humans and animals, behavioral responses to salient events are reflected in activation of the mesocorticolimbic reward valuation network.46,47 Mesolimbic dopamine neurons project from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) through the medial forebrain bundle (MFB). In animals, activation of excitatory low-affinity D1 receptors of the direct pathway and high-affinity D2 receptors of the indirect pathway is essential in driving motivated behaviors and learning.39 Dopaminergic dysfunction in several diseases in humans has been associated with behaviors such as impulsivity22 as well as increased pain sensitivity.25,62
The rat NAc shell has been shown to be vital in signaling both rewarding and aversive events.31,41 Activity in the NAc shell can therefore reflect value predictions (eg, gains and losses) in many diverse settings including, for example, monetary gambling.7 Unlike the NAc core, dopamine signals in the NAc shell of rats have been shown to play a differential and dynamic role in tracking reward information.55 In addition, modeling of VTA cell firing coupled with electrochemical dopamine detection in the rat has predicted that dopamine signaling may, respectively, arise from burst and constant firing in the NAc shell and core.20 Such hypothesized dynamic dopamine activity makes the NAc shell an area of interest for study in relation to changes in pain state.
We, and others, have previously reported that the saliency of relief of pain results in the activation of the mesolimbic dopamine pathway.44,46 Persistent aversive states, including pain, in humans and animals are known to alter tonic levels of dopamine in the NAc.67,68 Although tonic dopamine levels have been hypothesized to modulate the magnitude of phasic release events through activation of the dopamine D2 receptor (D2), to the best of our knowledge, this concept has never been directly tested in a pain condition.42 Elucidating the interplay of tonic and phasic dopaminergic signaling in the mesolimbic pathway is fundamental to understanding behaviors associated with many diseases that have altered dopaminergic tone such as schizophrenia30 and Parkinson disease,13 as well as in acute and chronic pain states.61
Dopamine signaling can occur over different temporal domains. Tonic dopamine levels are measured on a time scale of minutes, or longer.23 By contrast, phasic signals occur on second to subsecond time scales.66 The large differences in temporal dynamics associated with phasic and tonic signals present technical barriers that prevent the use of methods such as positron emission tomography and microdialysis in the same experimental setting.17,34 Fast-scan cyclic voltammetry (FSCVphasic) is capable of capturing phasic changes with low micrometer spatial resolution but cannot be used for tonic measurements due to background subtraction.29 Our laboratory has developed fast-scan controlled-adsorption voltammetry (FSCAVtonic), which can be used for tonic dopaminergic measurements using the same electrochemical probe as FSCVphasic with temporal resolution extending from minutes to days.3,4,16
Here, we used FSCAVtonic and FSCVphasic to measure tonic and phasic dopaminergic neurotransmission after induction of a noxious stimulus. We hypothesized that changes in baseline dopaminergic tone induced by pain would directly influence the magnitude of phasic dopamine events. We found that transient ongoing pain decreases tonic dopamine levels in the NAc shell, resulting in amplification of electrically evoked phasic dopamine release.
2. Materials and methods
Adult, male Sprague-Dawley rats (280-350 g; Envigo, Haslett, MI) were used in all experiments. All procedures were performed in accordance with the policies of the National Institutes of Health guidelines for laboratory animals under protocols approved by the University of Arizona Institutional Animal Care and Use Committee and were in accordance with International Association of the Study of Pain guidelines. Before surgery, animals were group-housed in a temperature- and humidity-controlled environment, on a 12-hour light–dark cycle (lights on at 07:00) with food and water provided ad libitum. All experiments were performed during the light stage of the cycle.
2.2. Electrodes and electrode placement
Carbon-fiber microelectrodes were constructed as previously described.65 Additional details can be found in the SI, available at, http://links.lww.com/PAIN/B44.
2.3. Anesthesia standardization
After electrode placement and before capsaicin experiments, the depth of anesthesia was standardized using a behavioral response. The latency to tail flick from an acutely noxious thermal stimulus was measured. Anesthesia was adjusted to elicit a tail-flick latency of approximately 6 seconds (6.3 ± 0.2 seconds, mean ± SEM).
2.4. Measurement of tonic dopamine levels
All dopamine measurements were made in animals under stable anesthesia while they were in a stereotaxic frame. We measured tonic dopamine levels using FSCAVtonic, a technique developed in our laboratory3,4 (see additional details in SI, available at, http://links.lww.com/PAIN/B44). Discrimination between dopamine and its metabolites was achieved by analyzing the 10th scan after the application of the holding period as previously reported.4
2.5. Procedure of transient ongoing pain and tonic dopamine measurements
Before pain induction, a 10-minute baseline was collected followed by application of saline (∼15-μL drop through transfer pipette) to the cornea of one eye. Dopamine levels were then recorded for 10 minutes. Capsaicin (Sigma-Aldrich, St. Louis, MO; 0.01%, 15 µL) was then applied to the same eye as saline. Ten minutes after the first capsaicin application and upon return of tonic dopamine levels to precapsaicin baselines, the same concentration and volume of capsaicin was administered a second time to the same eye. The same sequence was then applied to the alternate eye and dopamine levels were recorded (Fig. 1A). Application order to the left and right eyes was randomized between animals to control for potential lateralization effects.
2.6. Measurement of phasic dopamine signals
All dopamine measurements were made in animals with stable anesthesia while placed in a stereotaxic frame. Phasic dopamine measurements were made using FSCVphasic, a well-established technique for monitoring neurotransmitters in vivo53 (see SI for additional details, available at, http://links.lww.com/PAIN/B44).
2.7. Electrically evoked phasic dopamine measurement during transient ongoing pain
We designed our experimental paradigm to electrically evoke phasic dopamine release that coincided with a 2-minute period of ongoing pain after capsaicin (see below). Electrical stimulation of the MFB, which contains dopaminergic axons that project to the NAc, was chosen to elicit phasic dopamine release. Two important considerations were made when selecting the simulation parameters including: (1) the evoked dopamine release should be transient so that it could be produced repeatedly without change in magnitude every 2 minutes for the duration of the experiment; and (2) the stimulation pattern should mimic spontaneous burst firing66 rather than increasing the general activity of the neurons to ensure that we did not confound our results with increases in dopaminergic tone.23
Once every 2 minutes, the MFB was electrically stimulated (6 pulses, 30 Hz, 4-ms biphasic pulses, 380 µA) to produce a phasic dopamine release event in the NAc shell. Five baseline stimulated release events were recorded; then after application of saline to the same cornea, 5 more stimulated phasic release events were measured. Capsaicin was then applied to the same cornea and 5 more phasic release events were measured.
After experimentation, electrolytic lesions were made with the working electrode to allow visualization of the electrode tract. Electrolytic lesioning consisted of a slow increase in current applied to the carbon-fiber microelectrode (CFME) from 0 to 800 μA over the course of 10 minutes (see SI for additional details, available at, http://links.lww.com/PAIN/B44).
2.9. Data analysis
Tonic dopamine measurements were made relative to the first data point. The percent change was calculated by comparing the dopaminergic low point observed during the first 3 minutes of each recording to the tonic dopamine measurement made directly before treatment. The length of the hypodopaminergic state was established as the time after which 40% of the decrease in dopaminergic tone was recovered (see SI for more details, available at, http://links.lww.com/PAIN/B44). Phasic dopamine measurements were made relative to the average of the first 5 (baseline) evoked phasic release events. Percent change for phasic dopamine release was calculated by comparing the average of the 2 phasic events before saline or capsaicin application to the phasic release 1 minute after the application.
Generation of 2-dimensional color plots in LabVIEW software (National Instruments, Austin, TX), which show phasic dopamine release, are described in detail elsewhere.18 Briefly, time is represented on the abscissa and the voltammogram on the ordinate. Voltammetric current is represented in false color. Dopamine oxidation occurs at ∼0.6 V vs Ag/AgCl and is denoted with a horizontal dashed line. Representative voltammograms were taken from the vertical dashed line on the color plots and graphed vs potential.
Tonic dopamine data were analyzed using repeated-measures analysis of variance (ANOVA) tests. Where significant main effects were observed, post hoc analysis was conducted using Tukey procedure to correct for multiple comparisons. For phasic experiments, paired t-tests were used to compare the percent change data between saline and capsaicin (or saline and saline) subsequent applications within individual animals. For both tonic and phasic dopamine measurements, unpaired t-tests were used to compare the percent change in response to capsaicin treatment between ipsilateral or contralateral control groups (data are presented in the SI, available at, http://links.lww.com/PAIN/B44). All data are represented as mean ± SEM. Statistical analyses were completed using GraphPad Prism (GraphPad Software, San Diego, CA).
3.1. FSCAVtonic measures subminute changes in tonic dopamine
Tonic dopamine levels were measured in the NAc shell using FSCAVtonic in response to saline and capsaicin corneal treatment (Fig. 1A–C). First, after a 10-minute tonic dopamine baseline measurement (Fig. 1D), saline was applied (Fig. 1E, vertical dotted line) to one cornea, randomized to the ipsilateral or contralateral hemisphere of the CFME placement. Ten minutes after the initial saline application, capsaicin (Fig. 1F, vertical dotted line) was applied to the same cornea. After an additional 10 minutes, a second drop of capsaicin was given in the same eye (Fig. 1G). Results in Figure 1 include data from 10 animals.
3.2. A single application of capsaicin to the cornea decreases tonic dopamine levels
To determine whether capsaicin treatment had an effect on tonic dopamine levels, we calculated the maximum percent decrease during the first 3 minutes after each saline and capsaicin application. A significant main effect of treatment was observed (one-way ANOVA, F3, 27 = 5.18, P < 0.01; post hoc analysis revealed a significant effect of the capsaicin application when compared to baseline and saline data, P < 0.01 and P < 0.05, respectively). Saline did not significantly affect tonic dopamine levels when compared to baseline (Fig. 1H; 1 ± 4% decrease in tonic dopamine levels, post hoc analysis, P > 0.80). The capsaicin application significantly decreased dopamine levels (Fig. 1H, post hoc analysis, *P < 0.05), resulting in a 22 ± 8% maximum decrease. Dopaminergic minima were observed 1.4 ± 0.2 minutes after capsaicin application (Table S1, available at, http://links.lww.com/PAIN/B44) and the decrease lasted 2.0 ± 0.3 minutes (Figure S1, available at, http://links.lww.com/PAIN/B44). Application of a second capsaicin treatment to the same cornea resulted in a 9 ± 2% decrease in dopamine level (Fig. 1H). No significant change in dopamine level was observed when compared to saline (post hoc analysis, P > 0.40). No significant effects of capsaicin lateralization were observed (unpaired t test, P > 0.8, Figure S2, available at, http://links.lww.com/PAIN/B44).
3.3. FSCAVtonic measures subminute dopaminergic changes in the alternate cornea
Ten minutes after the second application of capsaicin to the first cornea, saline was applied to the alternate cornea (Fig. 1I). Using the same protocol as above, capsaicin was then applied twice consecutively at 10-minute intervals. The first application of capsaicin to the alternate eye produced a robust decrease in dopamine levels (Fig. 1J), whereas the second application of capsaicin to the alternate cornea had a significantly lower effect (Fig. 1K).
3.4. A hypodopaminergic response to capsaicin application is preserved in the alternate cornea
Saline application in the alternate cornea did not cause a significant change in dopamine levels (3 ± 1% decrease) when compared to the initial baseline recording (post hoc analysis, P > 0.75). However, a significant effect of treatment on tonic dopamine levels in the alternate eye was observed after capsaicin (Fig. 1L, one-way ANOVA, F3, 27 = 7.14, P < 0.01). A 22 ± 7% decrease was measured in response to capsaicin application in the alternate eye; this was significantly larger than the saline effect (post hoc analysis, **P < 0.01). Dopaminergic minima were observed 1.2 ± 0.1 minute after capsaicin application (Table S1, available at, http://links.lww.com/PAIN/B44). The decrease in dopamine level lasted 1.9 ± 0.3 minutes (Figure S1, available at, http://links.lww.com/PAIN/B44). Application of a second capsaicin treatment to this eye caused a 5 ± 1% decrease in dopamine levels, which was not significantly different from saline (Fig. 1L, post hoc analysis, P > 0.75) but was significantly different from change observed after the primary capsaicin application (Fig. 1L, post hoc analysis *P < 0.05).
3.5. Measurement of evoked phasic dopamine levels during pain-induced hypodopaminergic states
Having determined that a first application of capsaicin in either eye reliably produced a hypodopaminergic state of approximately 2 minutes, we next used FSCVphasic to determine whether phasic dopaminergic levels were affected during this period. Initial studies showed that electrical stimulation of the MFB (6 pulses, 30 Hz, 4-ms biphasic pulses, 380 µA) evoked dopamine release (∼5 nM) in the NAc shell and these stimulation parameters could be used repeatedly for an extended period without decrease in signal amplitude (Figure S3, available at, http://links.lww.com/PAIN/B44). The stimulation pattern was chosen to elicit dopamine events that mimicked transient dopamine signaling, which occurs as a result of neuronal burst firing23 (Fig. 2). Representative data demonstrate that electrically evoked dopamine release events were approximately the same magnitude as spontaneous, transient dopamine signals (Fig. 2A–D).
3.6. Two consecutive saline applications to the cornea do not alter evoked phasic dopamine signals
Experiments were designed so that electrically evoked, spontaneous-like, phasic dopamine events were recorded every 2 minutes (Fig. 3A). Stimulations were aligned such that a phasic release event occurred 1 minute before and 1 minute after treatment with saline or capsaicin. Before treatment, 5 baseline stimulations were measured over 10 minutes. In control experiments, 2 consecutive applications of saline were given in the same eye at 10-minute intervals, while phasic dopamine release was recorded every 2 minutes (Fig. 3B). The average electrically evoked phasic dopamine release that occurred during the 10-minute baseline and after the 2 consecutive saline applications in the control experiment were not significantly different (Figure S4, available at, http://links.lww.com/PAIN/B44, one-way ANOVA, F2, 12 = 1.64, P > 0.20).
3.7. Increased evoked phasic dopamine release is observed after application of capsaicin, but not saline, on the cornea
Baseline stimulations made before saline or capsaicin treatments were stable over the course of 10 minutes (Fig. 3C). Evoked phasic dopaminergic events that occurred after a corneal saline treatment were not significantly different from baseline (Fig. 3C and Figure S4, available at, http://links.lww.com/PAIN/B44, one-way ANOVA, F2, 12 = 8.01, P < 0.01, post hoc analysis, P > 0.70). Ten minutes after the saline treatment, capsaicin was applied to the same cornea. Evoked phasic dopamine release was increased 1 minute after the capsaicin application (Fig. 3C). In addition, the average evoked phasic release that occurred over the 10 minutes after capsaicin application was significantly higher than the average phasic dopamine release during the 10 minutes after saline application (Figure S4, available at http://links.lww.com/PAIN/B44, F2, 12 = 8.010, **P < 0.01). No effects were observed due to lateralization (Figure S5, available at http://links.lww.com/PAIN/B44, unpaired t test, P > 0.45). By 3 minutes after capsaicin treatment, evoked phasic dopamine release was no longer elevated. Similar results were observed after the first capsaicin application to the alternate cornea (Figure S6, available at http://links.lww.com/PAIN/B44).
3.8. Capsaicin causes a significant increase in the phasic dopaminergic percent change
The percent change in phasic dopamine release was calculated 1 minute after each saline or capsaicin treatment. In control experiments, the percent change in evoked dopamine release after the second saline application was not significantly different from the first (Fig. 3D, Wilcoxon test, P > 0.15). However, in experimental (saline then capsaicin treated) animals, the percent increase in phasic dopamine release after capsaicin was significantly higher than after saline treatment (Fig. 3E, Wilcoxon test, *P < 0.05). Phasic data for experimental animals in Figure 3 include data from 13 animals. Control data shown in Figure 3 represent 8 animals.
In this work, we investigated the effects of ongoing pain on dopamine signaling in the NAc shell. We used FSCAVtonic and FSCVphasic to make tonic and phasic measurements, respectively. Importantly, FSCAVtonic uses the same probes, instruments, and software as FSCVphasic, which is well established for monitoring phasic signals from neurotransmitters, especially dopamine, in vivo.49 The use of these techniques allowed us to measure, for the first time, both tonic and phasic signals during periods of transient ongoing pain. Our data show that (1) consistent with previous observations, the mesolimbic dopamine circuit reliably encodes salient events such as noxious stimuli; (2) ongoing pain produces time-locked and reversible decreases in tonic dopamine levels; and (3) that an electrical stimulus mimicking spontaneous phasic signaling during a period of low tonic dopamine levels results in significantly increased phasic dopamine release.
Phasic mesolimbic dopamine signaling is associated with salient events including relief of pain aversiveness.35 However, human studies have reported variable influences of pain on phasic dopamine signals in the NAc.10 Positron emission tomography imaging studies, also in humans, have demonstrated that a pain stimulus increases NAc dopamine release in healthy subjects but, surprisingly, not in patients with chronic pain.68 In addition, a noxious, but not nonnoxious, thermal stimulus applied to the hand caused decreased fMRI activations in the NAc.1 fMRI studies have also demonstrated a negative NAc signal change in response to the application of a noxious thermal stimulus and positive signal change upon the termination of the stimulus, suggestive of the saliency of pain onset and pain relief though this approach could not identify the relevant transmitters.8,9 Dopamine signals are altered in burning mouth syndrome28 and atypical facial pain27 in the human striatum. Application of a noxious stimulus showed an increase in fMRI BOLD signal at stimulus onset and a decrease at offset in patients with chronic pain,6 a finding suggestive of the relative relieving effects of acute pain on a background of chronic pain. Such observations are supportive of an interaction between phasic and tonic dopamine signaling in humans, but interpretation is complicated by many factors including, for example, the continued use of medications that likely altered the expression of receptors and neurotransmitters.
Preclinical investigations are yet to clarify the role of dopamine signaling in the NAc response to persistent pain states despite significant efforts. This is due, in part, to the use of multiple models that likely differ in their mechanistic responses after transient trauma, inflammatory injuries, or persistent neuropathic pain. An acute noxious stimulus (tail pinch) in rodents increased dopamine release in the NAc core, which lasted for the duration of the 3-second stimulus.15 In addition, this study found that dopamine release in the NAc shell was increased for a similar length of time after termination of the tail pinch. When intraperitoneal lactic acid was given to rodents, a decrease in dopaminergic tone was measured using microdialysis, which reached significance approximately 60 minutes after injection, likely reflecting persistent visceral pain.37 Electrophysiological studies revealed a decrease in VTA cell firing 5 days after peripheral nerve injury in the rat.52 Consistent with this, a decrease in dopamine levels in the rodent NAc was reported using microdialysis in response to neuropathic pain.52 However, other reports found no changes in NAc dopamine levels after peripheral nerve injury using microdialysis69 and indeed some reports have shown increased NAc shell dopamine levels in rats with neuropathic pain.56 Previous work from our laboratory and others used microdialysis to show increased NAc dopamine levels after relief of neuropathic and incisional pain in rats33,69 consistent with the conclusion that pain decreases dopamine in the NAc and that dopamine signals increase when pain is relieved.
The present experiments directly measured tonic and phasic NAc dopamine signals after induction of a period of ongoing pain that persists for approximately 2 minutes. Behavioral studies have shown that capsaicin produces a vigorous eye-wiping response in awake rats that resolves within 5 minutes presumably due to desensitization of the TRPV1 channel.12 The capsaicin-cornea model was chosen here largely for its known pain duration and the translational relevance of the pain state. In addition, the pain stimulus induced by capsaicin lasted long enough to capture both a tonic and phasic response. Notably, animals in this study were lightly anesthetized and the depth of anesthesia was standardized to a behavioral response (tail flick), which is an additional control not included in previous studies. FSCAVtonic measurements revealed that application of capsaicin to the cornea significantly decreased tonic dopamine levels in the NAc shell. Because dopaminergic tone is believed to be largely regulated by overall population activity of dopaminergic VTA neurons,23 this observation is consistent with data demonstrating inhibition of VTA dopaminergic cell firing in rodents during application of an acute noxious stimuli.14,63 Consistent with behavioral data, the observed decrease in tonic dopamine levels was significant but recovered within approximately 2 minutes. A second application of capsaicin to the same eye, however, elicited a smaller or absent dopaminergic response. This is likely explained by the well-known phenomenon of desensitization of the TRPV1 channel that mediates the capsaicin-induced activation of corneal afferents and is consistent with the time-related decrease in eye-wiping response after application of capsaicin to the cornea of awake animals.57 The correlation of electrophysiological, neurochemical, and behavioral observations thus provides strong support for the conclusion that mesolimbic dopamine signals encode salient stimuli regardless of conscious state of the animal. This conclusion is strengthened by the observation of a diminished effect on dopamine neurotransmission after desensitization of TRPV1 channels after a second capsaicin treatment on a previously tested cornea, but a prominent dopaminergic response to the first capsaicin treatment in the alternate (untested) eye.
The demonstration that capsaicin reliably produced a transient hypodopaminergic state allowed for direct investigation of the hypothesis that the magnitude of phasic signals may be inversely related to tonic levels (Fig. 4A). Independent regulation of cellular signals that underlie phasic and tonic dopamine levels in rats has been demonstrated.23 As such, relatively low tonic dopamine levels might allow phasic signals to be increased as a consequence of decreased D2 autoreceptor feedback inhibition.24,26,42 Previous work has demonstrated that D2 antagonism increases phasic release. In the presence of a D2 antagonist, D2 autoreceptor feedback inhibition is ineffective and thus the antagonist abolishes changes observed in response to consecutive electrical stimulation events.45 As such, testing the effects of D2 regulation on tonically altered changes in phasic dopamine release is not possible using this paradigm. Whether this inverse relationship occurs in conditions that reflect clinical states of pain has not previously been determined.
We found that evoked phasic dopamine release was increased and time-locked to the hypodopaminergic period (Fig. 4B). When stimulations were applied after the resolution of the capsaicin-induced hypodopaminergic period, the phasic signals returned to baseline. These data directly demonstrate the inverse relationship of tonic and phasic dopamine release in conditions of ongoing pain. Two limitations of this study are the use of only male rats as well as the assessment of dopamine levels in anesthetized, as opposed to awake, animals. We note, however, that the depth of anesthesia was standardized by the latency to a pain-induced behavioral reflex allowing comparisons to be made across animals. Future studies should include evaluations in female animals. Nevertheless, the implications of these findings are significant because phasic dopamine release is believed to underlie impulsivity,19 reward response,58 and decision making.54 Therefore disordered dopamine signaling could underlie comorbidities associated with chronic pain, such as the reward-related major depressive disorder, from which many chronic pain patients suffer.5,36 Cognitive deficits in decision-making tasks are seen in chronic pain patients using the Iowa Gambling Task2 and replicated in animal models of pain using the Rodent Gambling Task.48 Furthermore, cognitive flexibility, wherein responses are adapted to favor the most advantageous outcome, is impaired in chronic pain patients64 and in rodent pain models.38 This disordered habit-like responding has been associated with addiction,60 another comorbidity with chronic pain.51
It is notable that preclinical investigations show that pain symptoms can be treated with triple reuptake inhibitors, which increase tonic dopamine levels.43 Whether these drugs improve cognitive disorders in addition to improving pain remains to be determined. Further investigation of phasic and tonic interactions could also aid treatment of other dopaminergic disorders such as Parkinson disease, which has decreased NAc dopamine levels, as well as increased pain,11 impaired cognition,50 and increased impulsivity.32 Also, schizophrenia and psychosis, which are associated with decreased pain perception21 and impaired emotional responsivity,40 are often treated with dopaminergic antagonists.59 Thus, the dynamic relationship that we have confirmed between tonic and phasic dopamine signaling resulting from ongoing pain may underlie the cognitive pathology observed in multiple clinical states.
Conflict of interest statement
The authors have no conflicts of interest to declare.
Appendix A. Supplemental digital content
Supplemental digital content associated with this article can be found online at http://links.lww.com/PAIN/B44.
Supplemental video content
A video abstract associated with this article can be found at http://links.lww.com/PAIN/B45.
The authors thank Pablo I. Hernandez for his contributions to histological verification of electrode placement. This work was supported by NIH DA041809 (F.P., E.N.). Training grant support for T.A.G. was funded by NIH GM062584 (F.T.) and GM008804 (W.R.M.). The authors declare no financial conflicts of interest.
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