Persistent neuropathic pain selectively impairs hedonic and motivational aspects of eating: Insights from a mouse model.

Alcohol use disorder (AUD) and chronic pain are complex and debilitating conditions that are difficult to treat, lead to enormous economic costs, and excessive suffering. The difficulty in developing new treatments for AUD is partially due to the lack of consideration given to the wide array of factors that drive alcohol intake. Clinical data suggest that both men and women with chronic pain are more likely to develop alcohol use disorder and report using alcohol to deal with chronic pain. Additionally, it has been shown that self‐report of chronic pain correlates with alcohol relapse after a period of abstinence. These data led to the hypothesis that neural mechanisms that contribute to alcohol related behaviors are different in individuals that are also experiencing chronic pain. To test this hypothesis, we used a conditioned place preference (CPP) paradigm to model ethanol seeking in male and female rodents that had undergone either a spared nerve injury (SNI) model of chronic pain or a sham surgery. To determine a dose of ethanol that may be selectively rewarding to injured animals, we first tested the analgesic effects of multiple doses of ethanol on pain‐related behaviors in SNI and Sham mice. The higher doses of 1.0g/kg and 2.0g/kg (i.p.) of ethanol were anti‐allodynic in SNI mice and analgesic in sham mice. However, we found that the lower dose 0.5 g/kg of ethanol was able to fully reverse mechanical hypersensitivity in SNI animals, while not influencing mechanical thresholds in sham mice. Thus, we conditioned mice using 0.5g/kg of ethanol. We found this dose induced a modest conditioned place preference for the ethanol‐paired chamber in both SNI and Sham male mice. Mice then underwent extinction training for 1 week, during which time animals were exposed to the CPP apparatus without receiving any ethanol. To investigate relapse‐related behavior, we then tested whether painful stimulation would reinstate ethanol seeking behavior. We found that threshold hindpaw stimulation was able to reinstate ethanol seeking behavior in SNI, but not sham animals. This suggests that animals in chronic pain may associate alcohol with pain relief or that chronic pain animals may be more sensitive to stress induced reinstatement when pain is the stressor. We also tested the effect of drug induced reinstatement and found no differences between SNI and Sham mice, leading us to believe that differences found in pain induced reinstatement were selective to that modality. Ongoing work is aimed at determining the effect of ethanol on weight bearing behavior as well as the effect of chronic pain on ethanol seeking and relapse‐related behavior in female mice.

Ethanol Antiallodynia and Reward Seeking in Mice with Spared Nerve Injury

Chronic pain is associated with neuropsychiatric comorbidities characterized by impairments in cognitive and behavioral flexibility, yet the direct impact of chronic pain on reward-guided behavior remains poorly understood. Here, we investigated how chronic neuropathic pain altered sucrose-reinforced behavior across multiple behavioral assays with distinct cognitive-behavioral demands in male and female mice. Mice underwent spared nerve injury (SNI) or sham surgery and were tested in operant sucrose self-administration, reversal learning, and extinction training. The impact of acute painful stimulation on sucrose seeking was also assessed. SNI produced stable mechanical hypersensitivity without affecting acquisition or extinction of sucrose self-administration, indicating intact baseline acquisition and sucrose seeking. In contrast, chronic neuropathic pain selectively altered behavioral flexibility: SNI females exhibited faster acquisition of reversal learning, while SNI mice as a group showed impaired inhibition of responding on the previously reinforced lever during early reversal. Acute painful stimulation suppressed sucrose seeking in males, but not in females, independent of chronic pain status. At the neural level, painful mechanical stimulation differentially modulated medial prefrontal cortex (mPFC) activity, increasing infralimbic c-Fos expression in SNI mice while decreasing it in sham controls relative to non-stimulated animals. There was no evidence of chronic mPFC hyperactivity as indexed by ΔFosB expression. Together, these findings demonstrate that chronic neuropathic pain did not globally disrupt sucrose reward-related behavior, but instead selectively altered behavioral flexibility and pain–reward interactions in a sex-dependent manner, with accompanying alterations in mPFC engagement following aversive stimulation.

Antagonists of metabotropic glutamate receptors (mGluRs) have the potential to act as analgesic drugs that may help alleviate chronic pain. This study was done to look at the possible rewarding properties of the mGluR5 antagonist, fenobam, in a cognitive assay. Analgesic conditioned place preference (aCPP) was used to examine the effects of fenobam (30 mg/kg) and the prototypical mGluR5 antagonist, MPEP, and these effects were compared to those of a drug with known analgesic properties, morphine (10 mg/kg). In each experiment, one group of mice received spared nerve injury (SNI) surgery to model chronic pain; the other group received a control sham surgery. Both fenobam and MPEP induced preference in the SNI mice, such that SNI mice spent significantly more time in the mGluR5 antagonist-paired chamber compared to a vehicle-paired chamber. No such preference developed for sham mice. Morphine induced preference in male and female mice in both the SNI and sham groups. The results showed that fenobam and MPEP likely reduced on-going distress in the SNI mice, causing them to prefer the chamber paired with the drug compared to the vehicle-paired chamber. Since sham animals did not prefer the drug-paired chamber, these data demonstrate that mGluR5 antagonism is non-rewarding in the absence of pain-like injury.

Different genes involved in the amelioration of chronic neuropathic pain and comorbid anxiety by electroacupuncture with different intensities

Affective disorders, such as depression, are commonly associated with the development of chronic pain, but the underlying mechanisms still remain unclear. The dopaminergic system, located in the midbrain, is considered one of the regions where algesia and emotional processing overlap. This suggests a structural basis hypothesis for the comorbidity of chronic pain and depression, highlighting the interplay between nociceptive and affective processing. But there are more and more evidences show that somatic and head/facial pain involve different neuronal overlap. In previous study, the research show that VTA dopaminergic system involved in pIONT surgery induced depressive-like behaviors in mice. But there still no evidence shows if chronic somatic pain will induce depressive-like behaviors and which neuronal circle pathway is underly. In this study, we assessed depressive-like behaviors and performed artificial interference of VTA (ventral tegmental area) dopaminergic neurons in a mouse model of chronic peripheral neuropathic pain induced by the spared nerve injury (SNI) model. After a 4-week duration of hyperalgesia and allodynia resulting from SNI surgery, social withdraw and other depressive-like behaviors were observed in the SNI group. Furthermore, the dopaminergic cells' excitability in VTA were significantly increased in SNI mice. The excitability alteration was improved play a key role in the development and modulation of the chronic peripheral neuropathic pain-induced depressive-like behaviors. It has been shown pain and affections have structural and functional circuits to interact with each other, therefore the neuroplastic changes and functional role of VTA dopaminergic neurons within these circuits may serve as potential targets for understanding and therapeutically addressing the development of depressive-like symptoms accompanied by prolonged pain syndromes in humans.

Chronic pain is a debilitative disease affecting one in five adults globally and is a major risk factor for anxiety ( Goldberg and McGee, 2011; Lurie, 2018). Given the current dearth of available treatments for both individuals living with chronic pain and mental illnesses, there is a critical need for research into the molecular mechanisms involved in order to discover novel treatment targets. Cellular homeostasis is crucial for normal bodily functions, and investigations of this process may provide better understanding of the mechanisms driving the development of chronic pain. Using the spared nerve injury (SNI) model of neuropathic pain, we found contrasting roles for BECLIN-1 in the development of pain hypersensitivity and anxiety-like behaviors in a sex-dependent manner. Remarkably, we found that male SNI mice with impaired BECLIN-1 function demonstrated heightened mechanical and thermal hypersensitivity compared with male wild-type SNI mice, while female SNI mice with impaired BECLIN-1 function demonstrated similar thresholds to the female wild-type SNI mice. We also found that disruptions of BECLIN-1 prevented SNI-induced increases in anxiety-like behaviors in male mice. Our data thus indicate that BECLIN-1 is differentially involved in the nociceptive and emotional components of chronic pain in male but not female mice.

BackgroundThe application of pulsed radiofrequency (PRF) close to the dorsal root ganglia, or peripheral nerves, has been demonstrated to be effective for the treatment of chronic neuropathic pain conditions. The goal of this study was to investigate the analgesic effect of immediate PRF treatment after nerve injury and its possible cellular alterations in the dorsal horn of the spinal cord in rats with spared nerve injury (SNI).MethodsNeuropathic pain was achieved in a SNI neuropathic pain model by ligating and cutting the common peroneal and tibial branches of the left sciatic nerve, leaving the sural nerve intact. Wistar rats were divided into four groups that received different treatments, i.e., SNI and PRF for 6 min at 45 V (SNI + PRF-45 V), at 60 V (SNI + PRF-60 V), SNI alone, and sham groups. After the SNI surgery, each rat was immediately given the PRF treatment (500 kHz, rate of 2 Hz, 20 ms duration, temperature below 42 °C) on the left sciatic nerve 0.3–0.4 cm proximal to the injured site. The behavioral measurements included mechanical allodynia and cold allodynia of the ipsilateral hind paw and were performed during the 28 days that followed the SNI surgery and PRF treatment. Total extracellular signal-regulated kinase 1 and 2 (ERK1/2) and phospho-ERK1/2 were measured using Western blot in the ipsilateral spinal cord from animals in the different groups.ResultsThe three groups of rats with nerve injuries manifested a lower paw withdrawal threshold (PWT) in the behavioral measurement of mechanical allodynia and a shorter painful-behavior duration in the cold allodynia test over 28 days. Mechanical allodynia measurement showed that both the PRF-45 V and PRF-60 V treatment groups exhibited a more prominent antiallodynic effect than did the SNI group from days 1 to 28 after surgery. Similarly, in comparison with the SNI group, both the SNI + PRF-45 V and SNI + PRF-60 V groups had significant inhibition on the cold allodynia measurement from days 1 to 28 after surgery. Furthermore, the activation of the extracellular signal-regulated kinase 1 and 2 (ERK1/2) in the ipsilateral spinal dorsal horn of SNI rats was effectively inhibited in the SNI + PRF-45 V and SNI + PRF-60 V groups for 28 days after surgery.ConclusionsImmediate PRF application on the proximal nerve injury site provided a significant inhibition of neuropathic pain formation, accompanied by the inhibition of ERK activation.

Chronic pain and alcohol use disorder (AUD) are highly comorbid, and patients with chronic pain are more likely to meet the criteria for AUD. Evidence suggests that both conditions alter similar brain pathways, yet this relationship remains poorly understood. Prior work shows that the anterior insular cortex (AIC) is involved in both chronic pain and AUD. However, circuit-specific changes elicited by the combination of pain and alcohol use remain understudied. The goal of this work was to elucidate the converging effects of binge alcohol consumption and chronic pain on AIC neurons that send projections to the dorsolateral striatum (DLS). Here, we used the Drinking-in-the-Dark (DID) paradigm to model binge-like alcohol drinking in mice that underwent spared nerve injury (SNI), after which whole-cell patch-clamp electrophysiological recordings were performed in acute brain slices to measure intrinsic and synaptic properties of AIC→DLS neurons. In male, but not female, mice, we found that SNI mice with no prior alcohol exposure consumed less alcohol compared with sham mice. Electrophysiological analyses showed that AIC→DLS neurons from SNI-alcohol male mice displayed increased neuronal excitability and increased frequency of miniature excitatory postsynaptic currents. However, mice exposed to alcohol prior to SNI consumed similar amounts of alcohol compared with sham mice following SNI. Together, our data suggest that the interaction of chronic pain and alcohol drinking have a direct effect on both intrinsic excitability and synaptic transmission onto AIC→DLS neurons in mice, which may be critical in understanding how chronic pain alters motivated behaviors associated with alcohol.

Peripheral nerve injury promotes morphine-seeking behavior in rats during extinction

The effect and mechanism of low-dose esketamine in neuropathic pain-related depression-like behavior in rats

BACKGROUND: Pain-depression comorbidity has become a great burden to individuals and society. Nevertheless, the mechanisms underlying comorbid diseases have still not been fully revealed. Ultrasound-guided pulsed radiofrequency (PRF) on peripheral nerves, which produces remarkable analgesia via high-frequency electromagnetic energy, has become a main, minimally invasive treatment for chronic neuropathic pain. OBJECTIVES: The aim of this study was to explore the effect of ultrasound-guided PRF on the sciatic nerve of spared nerve injury (SNI) rats to relieve pain-induced depression. STUDY DESIGN: Experimental trial in rats. SETTING: The research took place in the Laboratory of The First Affiliated Hospital of Wenzhou Medical University. METHODS: Sixty male Wistar rats were randomly divided into a sham group, an SNI group, an SNI + free-PRF group, and an SNI + PRF group. Ultrasound-guided PRF was applied to the sciatic nerve on day 7 after SNI. The basal paw mechanical withdrawal threshold (PMWT) was evaluated as a measure for pain-related behavior, and a sucrose preference test was performed as a measure for depression-related behavior. The expression levels of spinal interferon regulatory factor 8 (IRF8) and of brain-derived neurotrophic factor (BDNF) in the prefrontal cortex (PFC) were also studied on days 21 and 42. RESULTS: The results showed that the PMWT was significantly decreased in rats following SNI operation; the decreased levels of PMWT were reversed in the SNI + PRF group after the application of PRF on the sciatic nerve on day 7. There were no statistically significant differences among the groups in the sucrose preference rate on day 21 after SNI operation. The sucrose preference rate on day 42 was higher in the SNI + PRF group than in the SNI + free-PRF group. Western blot and reverse transcription polymerase chain reaction also demonstrated that ultrasound-guided PRF on the sciatic nerve downregulated overexpression of spinal IRF8 and increased the levels of BDNF in the PFC. LIMITATIONS: This study was performed using only an SNI rat model which cannot represent all rodent neuropathic pain models. Only the short-term effectiveness of ultrasound-guided PRF on the sciatic nerve of SNI rats was investigated. The BDNF changes of other important brain areas were not taken into consideration in this study. CONCLUSIONS: These findings suggest that ultrasound-guided PRF on sciatic nerve could alleviate pain-induced depression. The mechanisms of this treatment may be involved in the downregulated spinal IRF8 and the increased BDNF in PFC. KEY WORDS: Neuropathic pain, depression, ultrasound, pulsed radiofrequency, interferon regulatory factor 8, brain-derived neurotrophic factor, spinal cord, prefrontal cortex

Memory impairment is a common comorbidity of chronic pain that significantly compromises patients' quality of life, yet the underlying neuronal circuit mechanisms remain poorly understood. Here, we employed a spared nerve injury (SNI) mouse model of chronic neuropathic pain and evaluated short-term memory performance using a novel object recognition test (NORT). Mice exhibited mechanical allodynia and object recognition memory (ORM) deficits 21 days following SNI surgery. Functional Magnetic Resonance Imaging (fMRI) analyses revealed a reduction in functional connectivity between the prelimbic cortex (PrL) and the lateral entorhinal cortex (LEC) in SNI mice. Viral tracing confirmed a direct monosynaptic anatomical projection from the PrL to the LEC, originating primarily from PrL layer 5 neurons. c-Fos immunostaining and in vivo calcium fiber photometry further demonstrated that both the PrL and LEC neurons were activated in response to novel object recognition, whereas these neuronal responses were significantly attenuated in SNI mice. Importantly, selective chemogenetic and optogenetic activation of the PrL-LEC pathway improved memory impairment in SNI mice without affecting pain sensitivity or locomotor activity. Chemogenetic inhibition of this pathway impaired ORM performance in normal mice. Our findings underscore the important role of PrL-LEC pathway hypoactivity in mediating short-term memory deficits associated with chronic pain and suggest this circuit as a promising therapeutic target for pain-related cognitive dysfunction.

Chronic pain is associated with maladaptive plasticity of corticolimbic brain regions. Perineuronal nets (PNNs), specialized extracellular matrix structures that surround neurons, regulate brain plasticity. We investigated the role of PNNs in the spared-nerve injury (SNI) model of neuropathic pain. We observed increased PNNs in the prefrontal cortex and nucleus accumbens of SNI mice. However, targeted degradation of PNNs in the prefrontal cortex exacerbated mechanical sensitivity in both SNI and sham mice without altering cold allodynia perception. By contrast, degradation of PNNs in the nucleus accumbens reduced allodynia in SNI mice. These findings indicate distinct regional roles of corticolimbic PNNs in neuropathic pain.

Men and women with chronic pain report increased alcohol use and are more likely to be diagnosed with alcohol use disorder. The relationship between alcohol use and pain is bidirectional. Alcohol is used as an analgesic, but chronic alcohol intake increases pain. Sex differences in the relationship between chronic pain and alcohol are reported in the clinical and preclinical literature, but due to this bidirectional relationship, it is challenging to investigate the mechanisms that contribute to these differences. Thus, animal models of chronic pain are needed to characterize the efficacy of ethanol as an analgesic in males and females. The current experiments tested the hypothesis that ethanol differentially reduces pain behaviors in male and female mice in chronic neuropathic pain. The spared nerve injury (SNI) model was used to investigate the analgesic effects of multiple doses of ethanol (0.5, 1, 2, g/kg i.p.) in male and female mice using von Frey and dynamic weight-bearing (DWB) assays. In both male and female mice, SNI led to robust allodynia and shifts in dynamic weight bearing. In male SNI mice, all three doses of ethanol fully reversed mechanical allodynia and shifts in DWB. In SNI females, only the highest dose (2.0g/kg) was fully antiallodynic in the von Frey assay, while shifts in weight bearing were reversed at the 1.0 and 2.0g/kg doses. The differences between male and females were not due to lower blood ethanol concentrations in female mice. These data indicate that while ethanol has antiallodynic and antinociceptive effects in male and female mice, the doses and time course of these effects are distinct. Studies investigating the relationship between pain and ethanol exposure in mice should consider sex as a key variable. These data also inform reported sex differences in rodent models of chronic pain and in chronic pain patients.