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Journal of Neuroimmune Pharmacology :... Jun 2024Chronic neuropathic pain precipitates a complex range of affective and behavioural disturbances that differ markedly between individuals. While the reasons for...
Chronic neuropathic pain precipitates a complex range of affective and behavioural disturbances that differ markedly between individuals. While the reasons for differences in pain-related disability are not well understood, supraspinal neuroimmune interactions are implicated. Minocycline has antidepressant effects in humans and attenuates affective disturbances in rodent models of pain, and acts by reducing neuroinflammation in both the spinal cord and brain. Previous studies, however, tend not to investigate how minocycline modulates individual affective responses to nerve injury, or rely on non-naturalistic behavioural paradigms that fail to capture the complexity of rodent behaviour. We investigated the development and resolution of pain-related affective disturbances in nerve-injured male rats by measuring multiple spontaneous ethological endpoints on a longitudinal naturalistic foraging paradigm, and the effect of chronic oral minocycline administration on these changes. Disrupted foraging behaviours appeared in 22% of nerve-injured rats - termed 'affected' rats - and were present at day 14 but partially resolved by day 21 post-injury. Minocycline completely prevented the emergence of an affected subgroup while only partly attenuating mechanical allodynia, dissociating the relationship between pain and affect. This was associated with a lasting downregulation of ΔFosB expression in ventral hippocampal neurons at day 21 post-injury. Markers of microglia-mediated neuroinflammation were not present by day 21, however proinflammatory microglial polarisation was apparent in the medial prefrontal cortex of affected rats and not in CCI minocycline rats. Individual differences in affective disturbances following nerve injury are therefore temporally related to altered microglial morphology and hippocampal neuronal activation, and are abrogated by minocycline.
Topics: Animals; Minocycline; Male; Rats; Neuroinflammatory Diseases; Rats, Sprague-Dawley; Neuralgia; Hyperalgesia; Individuality; Mood Disorders; Peripheral Nerve Injuries
PubMed: 38878098
DOI: 10.1007/s11481-024-10132-y -
Journal of Bodywork and Movement... Jul 2024Neck pain is a leading cause of disability worldwide. Visceral referred pain is a common form of disease-induced pain, with visceral nociception being referred to...
INTRODUCTION
Neck pain is a leading cause of disability worldwide. Visceral referred pain is a common form of disease-induced pain, with visceral nociception being referred to somatic tissues.
OBJECTIVE
The aim of this case report was to evaluate the immediate and long term effects of a novel osteopathic visceral technique (OVT) on pain and cervical range of motion (CROM) in a patient with nonspecific neck pain (NS-NP).
METHOD
A case of a 47-year-old female suffering with NS-NP for four months. The patient had sought physiotherapy treatment several times, and occasionally used anti-inflammatory medication to relieve symptoms. The patient presented muscle cervical tenderness and hyperalgesia over the spinous processes of C3-C4 spinal segments with limited CROM. A novel osteopathic visceral manipulation (OVM) technique was applied in the epigastric region targeting the pancreas. Immediately after the treatment, the patient reported reduction in pain evaluated with the numerical evaluation scale (NRS), and a clinically significant increase in pressure pain threshold (PPT) in C3 spinous process. Improvement in CROM was also observed. The post-treatment improvements have been maintained at 1-month of follow-up assessment.
CONCLUSION
A single OVT was effective in reducing cervical pain and increasing CROM in a patient with NS-NP caused by a viscerosomatic reflex. The results of this case study provides preliminary evidence that OVM can produce hypoalgesia in somatic tissues with segmentally related innervation. This finding encourages future research to gain a better understanding of the mechanisms of regional inhibitory interdependence involving the viscerosomatic reflexes of OVM.
Topics: Humans; Female; Neck Pain; Manipulation, Osteopathic; Middle Aged; Range of Motion, Articular; Pancreas; Cervical Vertebrae; Pain Measurement
PubMed: 38876625
DOI: 10.1016/j.jbmt.2024.02.028 -
European Journal of Pharmacology Jun 2024Pain is a common public health problem and remains as an unmet medical need. Currently available analgesics usually have limited efficacy or are accompanied by many...
Pain is a common public health problem and remains as an unmet medical need. Currently available analgesics usually have limited efficacy or are accompanied by many adverse side effects. To achieve satisfactory pain relief by multimodal analgesia, new combinations of nefopam and gabapentinoids (pregabalin/gabapentin) were designed and assessed in inflammatory, osteoarthritis and neuropathic pain. Isobolographic analysis was performed to analyze the interactions between nefopam and gabapentinoids in carrageenan-induced inflammatory pain, mono-iodoacetate-induced osteoarthritis pain and paclitaxel-induced peripheral neuropathic pain in mice. The anti-inflammatory effect and motor performance of monotherapy or their combinations were evaluated in the carrageenan-induced inflammatory responses and rotarod test, respectively. Nefopam (1, 3, 5, 10, 30 mg/kg, p.o.), pregabalin (3, 6, 12, 24 mg/kg, p.o.) or gabapentin (25, 50, 75, 100 mg/kg, p.o.) dose-dependently reversed mechanical allodynia in three pain models. Isobolographic analysis indicated that the combinations of nefopam and gabapentinoids exerted synergistic anti-nociceptive effects in inflammatory, osteoarthritis, and neuropathic pain mouse models, as evidenced by the experimental ED (median effective dose) falling below the predicted additive line. Moreover, the combination of nefopam-pregabalin/gabapentin alleviated carrageenan-induced inflammation and edema, and also prevented gabapentinoids-related sedation or ataxia by lowering their effective doses. Collectively, the co-administration of nefopam and gabapentinoids showed synergistic analgesic effects and may result in improved therapeutic benefits for treating pain.
PubMed: 38876275
DOI: 10.1016/j.ejphar.2024.176738 -
Pain Jun 2024The urocortin 1 (UCN1)-expressing centrally projecting Edinger-Westphal (EWcp) nucleus is influenced by circadian rhythms, hormones, stress, and pain, all known migraine...
Neuroanatomical evidence and a mouse calcitonin gene-related peptide model in line with human functional magnetic resonance imaging data support the involvement of peptidergic Edinger-Westphal nucleus in migraine.
The urocortin 1 (UCN1)-expressing centrally projecting Edinger-Westphal (EWcp) nucleus is influenced by circadian rhythms, hormones, stress, and pain, all known migraine triggers. Our study investigated EWcp's potential involvement in migraine. Using RNAscope in situ hybridization and immunostaining, we examined the expression of calcitonin gene-related peptide (CGRP) receptor components in both mouse and human EWcp and dorsal raphe nucleus (DRN). Tracing study examined connection between EWcp and the spinal trigeminal nucleus (STN). The intraperitoneal CGRP injection model of migraine was applied and validated by light-dark box, and von Frey assays in mice, in situ hybridization combined with immunostaining, were used to assess the functional-morphological changes. The functional connectivity matrix of EW was examined using functional magnetic resonance imaging in control humans and interictal migraineurs. We proved the expression of CGRP receptor components in both murine and human DRN and EWcp. We identified a direct urocortinergic projection from EWcp to the STN. Photophobic behavior, periorbital hyperalgesia, increased c-fos gene-encoded protein immunoreactivity in the lateral periaqueductal gray matter and trigeminal ganglia, and phosphorylated c-AMP-responsive element binding protein in the STN supported the efficacy of CGRP-induced migraine-like state. Calcitonin gene-related peptide administration also increased c-fos gene-encoded protein expression, Ucn1 mRNA, and peptide content in EWcp/UCN1 neurons while reducing serotonin and tryptophan hydroxylase-2 levels in the DRN. Targeted ablation of EWcp/UCN1 neurons induced hyperalgesia. A positive functional connectivity between EW and STN as well as DRN has been identified by functional magnetic resonance imaging. The presented data strongly suggest the regulatory role of EWcp/UCN1 neurons in migraine through the STN and DRN with high translational value.
PubMed: 38875125
DOI: 10.1097/j.pain.0000000000003294 -
Neuroreport Jun 2024Diabetic neuropathic pain (DNP) is one of the most prevalent symptoms of diabetes. The alteration of proteins in the spinal cord dorsal horn (SCDH) plays a significant...
OBJECTIVE
Diabetic neuropathic pain (DNP) is one of the most prevalent symptoms of diabetes. The alteration of proteins in the spinal cord dorsal horn (SCDH) plays a significant role in the genesis and the development of DNP. Our previous study has shown electroacupuncture could effectively relieve DNP. However, the potential mechanism inducing DNP's genesis and development remains unclear and needs further research.
METHODS
This study established DNP model rats by intraperitoneally injecting a single high-dose streptozotocin; 2 Hz electroacupuncture was used to stimulate Zusanli (ST36) and Kunlun (BL60) of DNP rats daily from day 15 to day 21 after streptozotocin injection. Behavioral assay, quantitative PCR, immunofluorescence staining, and western blotting were used to study the analgesic mechanism of electroacupuncture.
RESULTS
The bradykinin B1 receptor (B1R) mRNA, nuclear factor-κB p65 (p65), substance P, and calcitonin gene-related peptide (CGRP) protein expression were significantly enhanced in SCDH of DNP rats. The paw withdrawal threshold was increased while body weight and fasting blood glucose did not change in DNP rats after the electroacupuncture treatment. The expression of B1R, p65, substance P, and CGRP in SCDH of DNP rats was also inhibited after the electroacupuncture treatment.
CONCLUSION
This work suggests that the potential mechanisms inducing the allodynia of DNP rats were possibly related to the increased expression of B1R, p65, substance P, and CGRP in SCDH. Downregulating B1R, p65, substance P, and CGRP expression levels in SCDH may achieve the analgesic effect of 2 Hz electroacupuncture treatment.
PubMed: 38874969
DOI: 10.1097/WNR.0000000000002059 -
Cephalalgia : An International Journal... Jun 2024There is no defined preventive treatment protocol for persistent post-craniotomy headache. In several small case series and individual case reports onabotulinumtoxinA...
BACKGROUND
There is no defined preventive treatment protocol for persistent post-craniotomy headache. In several small case series and individual case reports onabotulinumtoxinA injected into the craniotomy scar has shown possible efficacy. What is lacking is long term follow-up and if focusing on the cranial suture lines along with the craniotomy scar can enhance improvement and provide more sustained benefit.
METHODS
Retrospective chart review with case series.
RESULTS
Four patients (three women, one man) with ICHD-3 defined persistent post craniotomy headache were treated using a novel onabotulinumtoxinA injection protocol. All the patients presented with continuous head pain of moderate to severe intensity. All had severe allodynia on the side of their craniotomy. All had significant reduction in quality of life. Our application of onabotulinumtoxinA involved injection into both the surgical scar and the transected/irritated cranial suture lines noted on neuroimaging and physical examination. With treatment all patients demonstrated significant benefit including a reduction in daily pain intensity (75%-100%), developing periods of pain freedom (2-7 days per week) and having a dramatic improvement in quality of life (close to 100% in all). The benefit was sustained for at least five years of follow-up.
CONCLUSION
From our case series it appears that injection not only along the painful craniotomy scar but into the involved cranial suture lines provides positive efficacy and sustained improvement in patients with persistent post craniotomy headache.
Topics: Humans; Female; Craniotomy; Botulinum Toxins, Type A; Male; Middle Aged; Adult; Cicatrix; Retrospective Studies; Follow-Up Studies; Cranial Sutures; Treatment Outcome
PubMed: 38870368
DOI: 10.1177/03331024241259452 -
The Journal of Pain Jun 2024Hand-holding reduces experimentally induced acute pain and buffers against the development of mechanical secondary hypersensitivity, an indirect proxy of central...
Hand-holding reduces experimentally induced acute pain and buffers against the development of mechanical secondary hypersensitivity, an indirect proxy of central sensitization. Here, we tested if verbal support from a stranger, a common occurrence in clinical contexts, exerts the same effects. In this preregistered study, 44 healthy female participants were assigned to an alone or support group whereby a supportive female stranger encouraged them through the painful procedure leading to secondary mechanical hypersensitivity. Mechanical hypersensitivity was measured via self-reports and by the size of the anteroposterior and mediolateral spread of mechanical hypersensitivity. We investigated the moderating role of attachment style on self-reports and the effects of support on skin conductance level, salivary cortisol, and pinprick-evoked potentials. We also tested whether theta/beta ratio in the resting-state electroencephalogram predicted mechanical hypersensitivity. Self-reported ratings and the late part of the pinprick-evoked potentials were reduced in the support group, but the spread of mechanical hypersensitivity was not. Attachment anxiety and avoidance moderated the self-reported intensity such that individuals with higher attachment anxiety and avoidance scores reported lower intensity ratings in the support group. No significant effect of the verbal support was observed on skin conductance level and salivary cortisol. The theta/beta ratio did not predict the extent of hypersensitivity. Our data indicate that, in women, verbal support during intense pain leading to hypersensitivity is effective on some behavioral outcomes, but altogether the lack of group differences in cortisol, self-reported stress, and skin conductance does not provide strong support for the stress-buffering hypothesis. PERSPECTIVE: Verbal support by a stranger during a painful procedure leading to secondary mechanical hypersensitivity attenuated the development of some measures of mechanical hypersensitivity and associated neural responses in healthy female participants. No evidence was found for the role of stress. DATA AVAILABILITY: The authors will make all data available upon request.
PubMed: 38866120
DOI: 10.1016/j.jpain.2024.104599 -
Biochemical and Biophysical Research... Sep 2024Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the...
Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the community suffer persistent neuropathic pain symptoms because current drug therapies may be suboptimal so there is a need for new therapeutic modalities. This study investigated the neuroprotective flavonoid, 6-methoxyflavone (6MF), as a potential therapeutic agent and gabapentin as the standard comparator, against neuropathic models. Thus, neuropathic-like states were induced in Sprague-Dawley rats using sciatic nerve chronic constriction injury (CCI) mononeuropathy and systemic administration of streptozotocin (STZ) to induce polyneuropathy. Subsequent behaviors reflecting allodynia, hyperalgesia, and vulvodynia were assessed and any possible motoric side-effects were evaluated including locomotor activity, as well as rotarod discoordination and gait disruption. 6MF (25-75 mg/kg) antagonized neuropathic-like nociceptive behaviors including static- (pressure) and dynamic- (light brushing) hindpaw allodynia plus heat/cold and pressure hyperalgesia in the CCI and STZ models. 6MF also reduced static and dynamic components of vulvodynia in the STZ induced polyneuropathy model. Additionally, 6MF reversed CCI and STZ suppression of locomotor activity and rotarod discoordination, suggesting a beneficial activity on motor side effects, in contrast to gabapentin. Hence, 6MF possesses anti-neuropathic-like activity not only against different nociceptive modalities but also impairment of motoric side effects.
Topics: Animals; Rats, Sprague-Dawley; Rats; Neuralgia; Flavones; Hyperalgesia; Male; Diabetes Mellitus, Experimental; Gabapentin; Nociception; Diabetic Neuropathies; Female; gamma-Aminobutyric Acid; Amines; Sciatic Nerve; Vulvodynia; Constriction; Neuroprotective Agents; Analgesics
PubMed: 38865809
DOI: 10.1016/j.bbrc.2024.150217 -
Molecular Neurobiology Jun 2024Chronic inflammatory pain caused by neuronal hyperactivity is a common and refractory disease. Kv3.1, a member of the Kv3 family of voltage-dependent K channels, is a...
Chronic inflammatory pain caused by neuronal hyperactivity is a common and refractory disease. Kv3.1, a member of the Kv3 family of voltage-dependent K channels, is a major determinant of the ability of neurons to generate high-frequency action potentials. However, little is known about its role in chronic inflammatory pain. Here, we show that although Kv3.1 mRNA expression was unchanged, Kv3.1 protein expression was decreased in the dorsal spinal horn of mice after plantar injection of complete Freund's adjuvant (CFA), a mouse model of inflammatory pain. Upregulating Kv3.1 expression alleviated CFA-induced mechanical allodynia and heat hyperalgesia, whereas downregulating Kv3.1 induced nociception-like behaviors. Additionally, we found that ubiquitin protein ligase E3 component n-recognin 5 (UBR5), a key factor in the initiation of chronic pain, binds directly to Kv3.1 to drive its ubiquitin degradation. Intrathecal injection of the peptide TP-CH-401, a Kv3.1 ubiquitination motif sequence, rescued the decrease in Kv3.1 expression and Kv currents through competitive binding to UBR5, and consequently attenuated mechanical and thermal hypersensitivity. These findings demonstrate a previously unrecognized pathway of Kv3.1 abrogation by UBR5 and indicate that Kv3.1 is critically involved in the regulation of nociceptive behavior. Kv3.1 is thus a promising new target for treating inflammatory pain.
PubMed: 38865078
DOI: 10.1007/s12035-024-04259-5 -
British Journal of Anaesthesia Jun 2024Chronic post-surgical pain (CPSP) significantly impacts patients' recovery and quality of life. Although environmental risk factors are well-established, genetic risk...
BACKGROUND
Chronic post-surgical pain (CPSP) significantly impacts patients' recovery and quality of life. Although environmental risk factors are well-established, genetic risk remains less understood.
METHODS
A meta-analysis of genome-wide association studies followed by partitioned heritability was performed on 1350 individuals across five surgery types: hysterectomy, mastectomy, abdominal, hernia, and knee. In subsequent animal studies, withdrawal thresholds to evoked mechanical stimulation were measured in Rag1 null mutant and wild-type mice after plantar incision and laparotomy. Cell sorting by flow cytometry tracked recruitment of immune cell types.
RESULTS
We discovered 77 genome-wide significant single-nucleotide polymorphism (SNP) hits, distributed among 24 loci and 244 genes. Meta-analysis of all cohorts estimated a SNP-based narrow-sense heritability for CPSP at ∼39%, indicating a substantial genetic contribution. Partitioned heritability analysis across a wide variety of tissues revealed enrichment of heritability in immune system-related genes, particularly those associated with B and T cells. Rag1 null mutant mice lacking both T and B cells exhibited exacerbated and prolonged allodynia up to 42 days after surgery, which was rescued by B-cell transfer. Recruitment patterns of B cells but not T cells differed significantly during the first 7 days after injury in the footpad, lymph nodes, and dorsal root ganglia.
CONCLUSIONS
These findings suggest a key protective role for the adaptive immune system in the development of chronic post-surgical pain.
PubMed: 38862382
DOI: 10.1016/j.bja.2024.04.053