Introduction

Chronic pain is a significant medical problem that affects ∼116 million American adults causing an economic burden of >$635 billion per year (Institute of Medicine, 2011; Egli et al., 2012). Unfortunately, effective treatment of chronic pain remains elusive as current pharmacological strategies often present with negative side effects and strong misuse potential (Jefferies, 2010). Currently, over 25% of people experiencing chronic pain report using alcohol to alleviate suffering (Riley and King, 2009) and those who consume alcohol to cope with pain report greater problematic alcohol use (Zale et al., 2015). Given the impact of both chronic pain and alcohol use disorder (AUD) on public health, an improved understanding of the interaction between these two conditions is critical for improving approaches aimed at prevention and treatment. Previous studies also suggest that the disruptions in the underlying neural circuitry for chronic pain and AUD are similar, yet this connection remains understudied (Watson et al., 1997; Stopponi et al., 2012).

Clinical studies show that the insular cortex (IC) is the most consistently activated region during induced pain experiences in humans (Tracey, 2011; Egli et al., 2012). In rodents, lesioning the IC reduces thermal hyperalgesia and mechanical allodynia (Benison et al., 2011; Coffeen et al., 2011; Zhuo, 2016). The IC is also significantly involved in the alcohol addiction cycle, notably the preoccupation/anticipation stage (Koob and Volkow, 2010; Campbell and Lawrence, 2021). Previous studies demonstrate that local inactivation of the IC disrupts seeking behaviors for alcohol (Ibrahim et al., 2019). However, studies implementing lesion or broad excitation/inhibition of IC do not provide insight into the disruption of specific insular neuron populations that project to distinct down-stream brain regions (Escobar et al., 1998; Jasmin et al., 2003; Benison et al., 2011; Coffeen et al., 2011). Moreover, studies that have investigated changes at the circuit level have focused primarily on IC projections to nucleus accumbens core and amygdala (Seif et al., 2013; Jaramillo et al., 2018b,a; Haaranen et al., 2020).

The anterior insular cortex (AIC), a subregion of IC, is responsible for integrating cognitive and sensory processes such as learning, memory, and sensory perception (Bermudez-Rattoni, 2004; Craig, 2011; Gal-Ben-Ari and Rosenblum, 2011; Zhuo, 2016; Gogolla, 2017). A major target of AIC innervation is the dorsolateral striatum (DLS; Hunnicutt et al., 2016; Munoz et al., 2018; Haggerty et al., 2022). The DLS plays a major role in governing habitual-directed behaviors (Corbit et al., 2012; Alloway et al., 2017; Munoz et al., 2018; Haggerty et al., 2022). Alcohol exposure selectively ablates µ-opioid receptor-mediated long-term synaptic depression at AIC inputs to the DLS (Munoz et al., 2018). Binge-like alcohol drinking produces enhanced ionotropic glutamate receptor-mediated transmission at AIC→DLS synapses that develop over the course of alcohol drinking, but this only occurs in males (Haggerty et al., 2022). However, disruption of AIC→DLS circuits evoked by chronic pain has not been studied. Historically, research in this area focuses on mechanisms of inflammatory and back pain in the ventral, but not dorsal, striatum (Baliki et al., 2012; Martikainen et al., 2015; Dirupo et al., 2021). Given that the DLS is directly connected to the AIC (Gerfen and Bolam, 2016), the AIC→DLS circuitry is of interest in the overlap of alcohol addiction and chronic pain. Here, we investigated the effects of chronic pain on binge-like alcohol drinking behavior and whether the combination of chronic pain and alcohol use alters the intrinsic and synaptic excitability of AIC→DLS neurons.

ResultsSNI induces mechanical allodynia and reduces binge-like alcohol intake in male mice

A schematic timeline of the experiments is shown in Figure 1A. To identify AIC neurons that project to the DLS, we injected red fluorescent RetroBeads into the right DLS (Fig. 1B,D). Fluorescently labeled neurons were found primarily in laminar layer 5 (L5) of the right AIC (Fig. 1C). Five days following RetroBeads injections, SNI or sham surgery was performed on the left hind leg (Fig. 1E). Animals were then acclimated to a reversed light/dark cycle for 7 d (Fig. 1A). We found that SNI induced significant mechanical allodynia at POD7 compared with sham surgery (Fig. 1H; rmANOVA: surgery, F(1,26) = 14.01, p < 0.001; time, F(1,26) = 67.62, p < 0.001; interaction, F(1,26) = 41.09, p < 0.001; Sidak's post hoc test: POD7 SNI vs sham, p < 0.001; SNI baseline vs POD7, p < 0.001).

Figure 1.

SNI model induces mechanical allodynia and reduces alcohol intake in mice. A, Schematic of the experimental timeline. B, Schematic depicting red retrograde tracer injection into the right DLS and a representative coronal brain section showing red fluorescent beads injection in the right DLS. C, Schematic depicting fluorescently labeled AIC→DLS neurons in the right AIC layer 5 and a representative coronal brain section showing the fluorescently labeled neurons in the right AIC layer 5. D, Locations of retrograde tracer injections. E, Schematic depicting the SNI model of neuropathic pain involving severing the tibial nerve and the common peroneal nerve while keeping the sural nerve intact. F, SNI mice had significantly lower alcohol intake across 15 drinking sessions (sham, N = 8; SNI, N = 8). Mice were given access to alcohol for 2 h from Monday to Thursday and 4 h on Friday. G, No difference in water intake for sham and alcohol animals across 15 drinking sessions (sham, N = 6; SNI, N = 6). H, Mechanical allodynia was observed on POD7 after SNI of the sciatic nerve (sham, N = 14; SNI, N = 14). I, No PWT difference observed from POD7 to POD28 for both water and alcohol drinking sham mice (sham–water, N = 6; sham–alcohol, N = 8). J, No PWT difference observed from POD7 to POD28 for both water and alcohol drinking SNI mice (SNI–water, N = 6; SNI–alcohol, N = 8). *p < 0.05. ***p < 0.001. N, animal number.

Animals subsequently started 3 weeks of DID (Fig. 1A). We previously demonstrated that our DID procedure can produce blood alcohol concentrations in excess of 80 mg/dl (Haggerty et al., 2022). We hypothesized that mice with SNI would consume higher amounts of alcohol during DID. Surprisingly, DID data showed that SNI animals consumed significantly less alcohol compared with sham mice across 3 weeks of DID (Fig. 1F; rmANOVA: surgery, F(1,14) = 7.2206, p = 0.0211; time, F(6.139,84.20) = 23.1815, p < 0.001; interaction, F(14,192) = 0.2605, p = 0.9968; homoscedasticity test, p = 0.159994; no significant difference in Sidak's post hoc analysis). However, no significant difference in water intake was detected between SNI and sham mice (Fig. 1G; rmANOVA: surgery, F(1,10) = 0.0177, p = 0.8962; time, F(3.714,37.14) = 38.7673, p < 0.001; interaction, F(14,140) = 0.2511, p = 0.9974). Analyses of drinking microstructure data revealed a significant interaction of lick duration and drinking session between sham and SNI mice in the 3  week alcohol DID (Fig. 2A; rmANOVA: surgery, F(1,14) = 1.889, p = 0.1909; time, F(3.997,53.10) = 8.987, p < 0.001; interaction, F(14,186) = 2.026, p = 0.0180). This indicates that lick duration for SNI mice was reduced compared with sham mice in the early stages of 3 week alcohol DID. However, no significant differences were detected in number of licks between sham and SNI mice in the 3 week alcohol DID (Fig. 2B; rmANOVA: surgery, F(1,14) = 1.253, p = 0.2818; time, F(5.694,75.65) = 11.71, p < 0.001; interaction, F(14,186) = 0.8557, p = 0.6079). Analyses of water drinking microstructure showed no significant differences between SNI and sham mice for lick duration (Fig. 2C; rmANOVA: surgery, F(1,10) = 0.6501, p = 0.439; time, F(3.260,27.71) = 4.353, p = 0.011; interaction, F(14,119) = 0.7555, p = 0.714) or number of licks (Fig. 2D; rmANOVA: surgery, F(1,10) = 1.306, p = 0.280; time, F(2.215,18.83) = 4.052, p = 0.031; interaction, F(14,119) = 0.8524, p = 0.611). Overall, this shows that SNI was not inducing a disruption in the animals' ability to consume from bottles with lickometers.

Figure 2.

Drinking microstructure analyses of number of licks and lick duration for 3 week DID animals. A, There is a significant interaction of surgery and drinking session on alcohol lick duration. B, SNI and sham group showed no statistical difference in number of alcohol licks. C, D, SNI and sham mice showed no significant differences in (C) water lick durations or (D) number of water licks (sham–water, N = 6; sham–alcohol, N = 8; SNI–water, N = 6; SNI–alcohol, N = 8). N, animal number.

At completion of DID, no changes to the PWT were observed in sham mice (Fig. 1I; rmANOVA: fluid, F(1,12) = 0.2727, p = 0.611; time, F(1,12) = 2.080, p = 0.175; interaction, F(1,12) = 2.167, p = 0.167). There is no observed difference between SNI–alcohol and SNI–water animals between POD7 and POD28 either, suggesting that 3 weeks of alcohol exposure did not affect mechanical allodynia (Fig. 1J; rmANOVA: fluid, F(1,12) = 0.9217, p = 0.356; time, F(1,12) = 2.107, p = 0.172; interaction, F(1,12) = 0.8914, p = 0.364). Altogether, these data demonstrate that SNI-induced mechanical allodynia persists from POD7 through POD28 across both alcohol and water drinking animals. Overall, data from DID experiments did not support our hypothesis as injured animals (SNI) drank significantly less alcohol than uninjured (sham) controls.

SNI induces mechanical allodynia but has no effect on DID alcohol consumption in female mice

We next tested the effects of SNI on DID in female mice. As in male mice, SNI female mice showed significant mechanical allodynia 7 d after surgery, and it persisted until POD28 compared with sham female mice (Fig. 3A; rmANOVA: surgery, F(1,10) = 15.65, p = 0.003; time: F(2,20) = 18.61, p < 0.001; interaction: F(2,20) = 13.43, p < 0.001; Sidak's post hoc test: POD7 SNI vs sham, p < 0.001; POD28 SNI vs sham, p < 0.001; SNI baseline vs POD7, p < 0.001; SNI baseline vs POD28, p < 0.001; SNI POD7 vs POD28, p > 0.999). However, SNI females consumed a similar amount of alcohol compared with sham females across the 3 week DID (Fig. 3B; rmANOVA: surgery, F(1,10) = 0.1756, p = 0.684; time, F(4.310,43.10) = 19.05, p < 0.001; interaction, F(14,140) = 0.3988, p = 0.973), which is not what we observed in SNI male mice. While this lack of difference in DID–alcohol consumption between sham and SNI female mice is interesting and needs further investigation, we focused our attention on male mice for this study.

Figure 3.

SNI has no effect on DID–alcohol consumption in female mice. A, SNI female mice showed significantly decreased PWT on POD7 and POD28 compared with baseline after surgery. B, SNI and sham female mice had similar alcohol intake (sham, N = 6; SNI, N = 6). **p < 0.01. ***p < 0.001. N, animal number.

Both SNI and sham male mice display alcohol placed preference

To examine if reduced alcohol intake in SNI mice was due to a pain-induced reduction in reward value of alcohol, we measured CPP for alcohol reward on a separate cohort of animals (Fig. 4A). As in our DID cohort, SNI induced significant mechanical allodynia at POD7 (Fig. 4B; rmANOVA: surgery, F(1,29) = 17.74, p < 0.001; time, F(1,29) = 158.1, p < 0.001, interaction, F(1,29) = 144.6, p < 0.001; Sidak's post hoc test: SNI baseline vs POD7, p < 0.001; POD7 SNI vs sham, p < 0.001). Both sham and SNI mice displayed significantly increased alcohol preference during the test session compared with baseline. However, there was no statistical difference detected between SNI and sham mice's preference scores on test day (Fig. 4C,D; rmANOVA: surgery, F(1,29) = 0.03549, p = 0.8519; session, F(1,29) = 24.11, p < 0.001; interaction, F(1,29) = 0.5710, p = 0.4560). Total distance traveled and velocity across all saline and alcohol conditioning sessions were not significantly different, indicating no change in locomotive behaviors (Fig. 4E–H). These data suggest that reward value of alcohol and alcohol-induced locomotion are similar for both sham and SNI mice and do not contribute to the observed decrease of DID alcohol intake in SNI animals.

Figure 4.

SNI and sham mice both showed alcohol place preference. A, Schematic of the experimental timeline. B, Mechanical allodynia was observed on POD7 after SNI surgery. C, Example animal heatmap for alcohol CPP assay during baseline and test sessions. D, Both sham and SNI mice showed increased alcohol preference during test session compared with baseline session. E, No difference observed in total distance moved during saline conditioning sessions between sham and SNI mice. F, No difference observed in total distance moved during alcohol conditioning sessions between sham and SNI mice. G, No difference observed in velocity during saline conditioning sessions between sham and SNI mice. H, No difference observed in velocity during alcohol conditioning sessions between sham and SNI mice (sham, N = 16; SNI, N = 15). ***p < 0.001. N, animal number.

SNI and sham male mice do not display anhedonia-like behaviors

Previous studies suggested chronic pain leads to development of negative emotional states like anhedonia (Garland et al., 2020; Markovic et al., 2021). To test whether reduced alcohol drinking in SNI mice was due to increased anhedonia, we performed a modified DID schedule consisting of a single week of alcohol exposure followed by 1 week of saccharin (0.2% w/v) drinking in SNI and sham mice (Fig. 5A). SNI mice showed significant mechanical allodynia 7 d after surgery compared with the baseline (Fig. 5B; rmANOVA: surgery, F(1,22) = 5.377, p = 0.03; time, F(1,22) = 19.05, p < 0.001; interaction, F(1,22) = 19.09, p < 0.001; Sidak's post hoc test: SNI baseline vs POD7, p < 0.001; POD7 SNI vs sham, p < 0.001). During the first week of DID, SNI animals consumed significantly less alcohol compared with sham animals (Fig. 5C; rmANOVA: surgery, F(1,22) = 9.105, p = 0.006; time, F(4,88) = 18.07, p < 0.001; interaction, F(4,88) = 0.4559, p = 0.768), consistent with our 3 week DID experiments (Fig. 1F). Interestingly, SNI and sham animals consumed the same amount of saccharin following alcohol DID (Fig. 5D. rmANOVA: surgery, F(1,22) = 0.6946, p = 0.414; time, F(2.180,47.95) = 91.62, p < 0.001; interaction, F(4,88) = 1.643, p = 0.171). Comparison of baseline alcohol drinking from this saccharin cohort with our 3 week DID animals (Fig. 1F) revealed no significant differences (Fig. 5E; rmANOVA: cohorts, F(1,18) = 2.407, p = 0.138; session, F(2.432,43.18) = 16.33, p < 0.001; interaction, F(4,71) = 1.009, p = 0.409; Fig. 5F; rmANOVA: cohorts, F(1,18) = 2.648, p = 0.121; session, F(2.949,51.60) = 19.82, p < 0.001; interaction, F(4,70) = 0.9534, p = 0.439). These data indicate that reduced DID alcohol consumption in SNI animals is not driven by anhedonia (Verharen et al., 2023).

Figure 5.

SNI and sham mice had no difference in saccharin intake. A, Schematic of the experimental timeline. B, Mechanical allodynia was observed on POD7 after SNI surgery. C, SNI mice showed lower alcohol intake during the first week of alcohol DID compared with sham mice. D, SNI and sham mice showed similar saccharin intake during the second week of saccharin DID (sham, N = 12; SNI, N = 12). E, SNI mice in saccharin drinking cohorts and 3 week DID cohorts drank similar amount of alcohol (3 week DID, N = 8; saccharin drinking cohorts, N = 12). F, Sham mice in saccharin drinking cohorts and 3 week DID cohorts drank similar amount of alcohol (3 week DID, N = 8; saccharin drinking cohorts, N = 12). *p < 0.05. **p < 0.01. ***p < 0.001. N, animal number.

SNI in combination with alcohol increases intrinsic excitability of AIC→DLS neurons

After animals finished 3 weeks of DID, we performed whole-cell electrophysiology recordings on retrogradely labeled L5 AIC→DLS neurons in acute brain slices (bregma 2.46–1.98 mm; Fig. 6A–D). Recording analyses revealed a drinking and pain interaction, indicating that AIC→DLS neurons from SNI–alcohol mice displayed an increased frequency of action potentials in response to depolarizing current steps compared with all other mice (Fig. 6E,F; rmANOVA: current, F(12,900) = 902.3, p < 0.001; fluid, F(1,75) = 3.016, p = 0.087; surgery, F(1,75) = 4.563, p = 0.036; current × fluid, F(12,900) = 1.829, p = 0.040; current × surgery, F(12,900) = 4.713, p < 0.001; fluid × surgery, F(1,75) = 4.302, p = 0.042; current × fluid × surgery, F(12,900) = 4.421, p < 0.001). Analysis of action potentials evoked by a 400 pA step-current injection revealed that AIC→DLS neurons from SNI–alcohol mice fired significantly more action potentials compared with neurons from all other groups (Fig. 6G; two-way ANOVA: fluid, F(1,75) = 2.467, p = 0.120; surgery, F(1,75) = 6.632, p = 0.012; interaction, F(1,75) = 5.894, p = 0.018; Tukey's test: sham–water vs SNI–alcohol, p = 0.027; SNI–water vs SNI–alcohol, p = 0.025; sham–alcohol vs SNI–alcohol, p = 0.002; Table 1). AIC→DLS neurons from alcohol-DID mice displayed a significantly depolarized resting membrane potential compared with mice that consumed water, but no statistical difference between SNI–alcohol and sham–alcohol AIC→DLS neurons was detected (Fig. 6H; two-way ANOVA: fluid, F(1,75) = 4.900, p = 0.030; surgery, F(1,75) = 0.5395, p = 0.465; interaction, F(1,75) = 2.902, p = 0.093; Table 1). No significant main differences were detected in action potential threshold potential or input resistance across the four experimental groups (Fig. 6I,J; Table 1). Together, these results suggest that the interaction of SNI and alcohol consumption increases intrinsic excitability of AIC→DLS neurons.

Figure 6.

The combination of SNI and alcohol consumption increases the intrinsic excitability of AIC→DLS neurons. Representative images showing fluorescent retrograde labeling of an AIC→DLS neuron recorded in AIC at 4× under (A) bright view and (B) fluorescent view; at 60× under (C) bright view and (D) fluorescent view. E, Example traces of current-evoked action potential firing from AIC→DLS neurons from sham–water (gray), sham–alcohol (black), SNI–water (orange), and SNI–alcohol (red) animals. F, Frequency–input (FI) current curves showing that the frequency of action potential firing of AIC→DLS neurons in response to depolarizing current steps in SNI–alcohol mice (N = 6, n = 22) is significantly higher compared with neurons from sham–water (N = 6, n = 16), SNI–water (N = 5, n = 19), and sham–alcohol (N = 7, n = 22) mice (asterisks represent significant difference between cells from sham–alcohol and SNI–alcohol group). G, AIC→DLS neurons from SNI–alcohol mice had more number of action potentials after injecting 400 pA current compared with neurons from all other groups. H, Alcohol drinking mice displayed a depolarized resting membrane potential compared with water drinking mice. There was no difference in (I) threshold potential or (J) input resistance. *p < 0.05. **p < 0.01. ***p < 0.001. N, animal number; n, cell number.

Table 1.

Subthreshold and firing properties of AIC→DLS neurons from sham–water, SNI–water, sham–alcohol, and SNI–alcohol groups of animals

The combination of SNI and alcohol consumption increases the frequency of mEPSCs of AIC→DLS neurons

We next tested for differences in excitatory synaptic transmission onto AIC→DLS neurons by recording mEPSCs in the AIC across the four experimental groups (Fig. 7A). A significant increase in mEPSC frequency was detected in AIC→DLS neurons from SNI–alcohol mice compared with that from SNI–water and sham–alcohol groups (Fig. 7B; two-way ANOVA: fluid, F(1,57) = 1.097, p = 0.299; surgery, F(1,57) = 4.443, p = 0.039; interaction, F(1,57) = 8.822, p = 0.004; Tukey's test: SNI–water vs SNI–alcohol, p = 0.03; sham–alcohol vs SNI–alcohol, p = 0.003). No statistical differences were observed in the amplitude of mEPSCs (Fig. 7C; two-way ANOVA: fluid, F(1,57) = 1.936, p = 0.170; surgery, F(1,57) = 1.574, p = 0.215; interaction, F(1,57) = 0.009343, p = 0.923). Increased mEPSC frequency without a change in mEPSC amplitude indicates that SNI plus alcohol consumption enhances presynaptic glutamate release onto AIC→DLS neurons. It is likely that enhanced presynaptic release of the glutamate is a contributing factor in the increased excitability of AIC→DLS neurons recorded from SNI–alcohol mice.

Figure 7.

The combination of SNI and alcohol consumption increases the mEPSC frequency of AIC→DLS neurons. A, Example traces of mEPSCs from AIC→DLS neurons from sham–water (gray, N = 6, n = 16), sham–alcohol (black, N = 5, n = 13), SNI–water (orange, N = 6, n = 14), and SNI–alcohol (red, N = 6, n = 18) mice. B, Neurons from SNI–alcohol mice displayed an increased frequency of mEPSCs compared with those from the sham–alcohol and SNI–water groups. C, No difference observed in the amplitude of mEPSCs among all four groups. *p < 0.05. **p < 0.01. N, animal number; n, cell number.

AIC→DLS neuronal excitability is not significantly altered in male mice after 1 week of DID

We next determined if intrinsic properties of AIC→DLS neurons are altered earlier in the DID paradigm. Therefore, we performed electrophysiology recordings on SNI and sham male mice after only 1 week of DID. Consistent with the 3 week DID findings, SNI mice drank significantly less alcohol compared with sham mice during this 1 week DID (Fig. 8A; rmANOVA: surgery, F(1,9) = 5.421, p = 0.045; time, F(2.867,25.80) = 11.83, p < 0.001; interaction, F(4,36) = 1.084, p = 0.379). SNI and sham mice consumed similar amount of water throughout the week (Fig. 8B; rmANOVA: surgery, F(1,6) = 0.1683, p = 0.696; time, F(2.111,12.67) = 20.37, p < 0.001; interaction, F(4,24) = 1.381, p = 0.270). SNI mice showed mechanical allodynia 7 d after surgery (Fig. 8D; rmANOVA: surgery, F(1,17) = 10.15, p = 0.005; time, F(1,17) = 21.76, p = 0.001; interaction, F(1,17) = 27.28, p < 0.001; Sidak's post hoc test: SNI baseline vs POD7, p < 0.001; POD7 SNI vs sham, p < 0.001). Our recording analyses revealed no significance effects of fluid, surgery, or fluid–surgery interaction on action potential firing (Fig. 8C; rmANOVA: current, F(12,816) = 1029, p < 0.001; fluid, F(1,68) = 0.001248, p = 0.972; surgery, F(1,68) = 2.135, p = 0.149; current × fluid, F(12,816) = 0.07712, p > 0.999; current × surgery, F(12,816) = 2.013, p = 0.021; fluid × surgery, F(1,68) = 2.258, p = 0.138; current × fluid × surgery, F(12,816) = 2.427, p = 0.004). In addition, no significant difference was detected in resting membrane potential or threshold potential across the four experimental groups (Fig. 8E,F). However, there is a main surgery difference in input resistance, indicating that SNI mice had significantly lower input resistance than sham mice, regardless of fluid intake (Fig. 8G; two-way ANOVA: fluid, F(1,68) = 0.2036, p = 0.653; surgery, F(1,68) = 4.824, p = 0.031; interaction, F(1,68) = 1.328, p = 0.253). Overall, these data indicate that AIC→DLS neuronal excitability is unchanged by SNI and only 1 week of alcohol DID.

Figure 8.

The combination of SNI and alcohol has no significant effect on the AIC→DLS neuronal excitability after 1 week DID. A, SNI mice had significantly lower alcohol intake compared with sham mice (sham, N = 6; SNI, N = 5). B, SNI and sham mice had similar water intake during 1 week DID (sham, N = 4; SNI, N = 4). C, All four groups of animals showed similar action potential firing frequency of AIC→DLS neurons in response to depolarizing current steps. D, SNI mice showed significantly lower PWT on POD7 compared with baseline. E, There is no difference in resting membrane potential among the four groups. F, There is no difference in threshold potential among the four groups. G, SNI mice show significantly lower input resistance compared with sham group mice (sham–water, N = 4, n = 18; SNI–water, N = 4, n = 20; sham–alcohol, N = 5, n = 18; SNI–alcohol, N = 4, n = 16). *p < 0.05. **p < 0.01. ***p < 0.001. N, animal number; n, cell number.

Alcohol exposure prior to SNI ablates the differences in DID alcohol intake and AIC→DLS neuronal excitability observed in mice with no alcohol pre-exposure prior to surgery

Pre-existing substance use disorders contribute to higher levels of pain after injury (Turk, 1997), which may play a role in the continuation of the alcohol drinking problems (Brennan et al., 2005). Individuals with current alcohol drinking problems are m