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Chemotherapy-induced peripheral neuropathy (CIPN) is a somatosensory small fiber axonopathy in cancer patients receiving any of a variety of widely-use antitumor agents. CIPN can lead to long-lasting neuropathic pain that limits the dose or length otherwise life-saving cancer therapy. Accumulating evidence over the last two decade indicates that many chemotherapeutic agents cause mitochondrial injury in the peripheral sensory nerves by disrupting mitochondrial structure and bioenergetics, increasing nitro-oxidative stress and altering mitochondrial transport, fission, fusion and mitophagy. The accumulation of abnormal and dysfunctional mitochondria in sensory neurons are linked axonal growth defects resulting in loss of intraepidermal nerve fibers in the hands and feet, increased spontaneous discharge and the sensitization of peripheral sensory neurons that provoke and promote changes in the central nervous system that establish chronic neuropathic pain. This has led to the propose mitotoxicity theory of CIPN. Strategies that improve mitochondrial function have shown success in preventing and reversing CIPN in pre-clinical animal models and have begun to show some progress toward translation to the clinic. In this review, we will review the evidence for, the causes and effects of and current strategies to target mitochondrial dysfunction in CIPN.
Learn More >The General Health Questionnaire 12 (GHQ-12) is a short easy-to-use scale to assess psychological distress. The GHQ-12 has not been validated for assessing psychological distress in patients with chronic low back pain (LBP).
Learn More >Interstitial cystitis is associated with neurogenic inflammation and neuropathic bladder pain. Dual leucine zipper kinase (DLK) expressed in sensory neurons is implicated in neuropathic pain. We hypothesized that neuronal DLK is involved in the regulation of inflammation and nociceptive behavior in cystitis. Mice deficient in DLK in sensory neurons (cKO) were generated by crossing DLK floxed mice with mice expressing Cre recombinase under Advillin promoter. Cystitis was induced by cyclophosphamide (CYP) administration in mice. Nociceptive behavior, bladder inflammation, and pathology were assessed following cystitis induction in control and cKO mice. The role of DLK in CYP-induced cystitis was further determined by pharmacological inhibition of DLK with GNE-3511. Deletion of neuronal DLK attenuated CYP-induced pain-like nociceptive behavior and suppressed histamine release from mast cells, neuronal activation in the spinal cord, and bladder pathology. Mice deficient in neuronal DLK also showed reduced inflammation induced by CYP and reduced c-Jun activation in the dorsal root ganglia (DRG). Pharmacological inhibition of DLK with GNE-3511 recapitulated the effects of neuronal DLK depletion in CYP treatment mice. Our study suggests that DLK is a potential target for the treatment of neuropathic pain and bladder pathology associated with cystitis.
Learn More >Low temperatures can be fatal to insects, but many species have evolved the ability to cold acclimate, thereby increasing their cold tolerance. It has been previously shown that larvae perform cold-evoked behaviors under the control of noxious cold-sensing neurons (nociceptors), but it is unknown how the nervous system might participate in cold tolerance. Herein, we describe cold-nociceptive behavior among 11 drosophilid species; we find that the predominant cold-evoked larval response is a head-to-tail contraction behavior, which is likely inherited from a common ancestor, but is unlikely to be protective. We therefore tested the hypothesis that cold nociception functions to protect larvae by triggering cold acclimation. We found that Class III nociceptors are sensitized by and critical to cold acclimation and that cold acclimation can be optogenetically evoked, cold. Collectively, these findings demonstrate that cold nociception constitutes a peripheral neural basis for larval cold acclimation.
Learn More >Acute pain management in patients with opioid use disorder who are maintained on methadone presents unique challenges due to high levels of opioid tolerance in this population. This randomized controlled study assessed the analgesic and abuse liability effects of escalating doses of acute intravenous (IV) hydromorphone versus placebo utilizing a validated experimental pain paradigm, quantitative sensory testing (QST).
Learn More >The treatment of neuropathic and central pain still remains a major challenge. Thalamic deep brain stimulation (DBS) involving various target structures is a therapeutic option which has received increased re-interest. Beneficial results have been reported in several more recent smaller studies, however, there is a lack of prospective studies on larger series providing long term outcomes. Forty patients with refractory neuropathic and central pain syndromes underwent stereotactic bifocal implantation of DBS electrodes in the centromedian-parafascicular (CM-Pf) and the ventroposterolateral (VPL) or ventroposteromedial (VPM) nucleus contralateral to the side of pain. Electrodes were externalized for test stimulation for several days. Outcome was assessed with five specific VAS pain scores (maximum, minimum, average pain, pain at presentation, allodynia). The mean age at surgery was 53.5 years, and the mean duration of pain was 8.2 years. During test stimulation significant reductions of all five pain scores was achieved with either CM-Pf or VPL/VPM stimulation. Pacemakers were implanted in 33/40 patients for chronic stimulation for whom a mean follow-up of 62.8 months (range 3-180 months) was available. Of these, 18 patients had a follow-up beyond four years. Hardware related complications requiring secondary surgeries occurred in 11/33 patients. The VAS maximum pain score was improved by ≥50% in 8/18, and by ≥30% in 11/18 on long term follow-up beyond four years, and the VAS average pain score by ≥50% in 10/18, and by ≥30% in 16/18. On a group level, changes in pain scores remained statistically significant over time, however, there was no difference when comparing the efficacy of CM-Pf versus VPL/VPM stimulation. The best results were achieved in patients with facial pain, poststroke/central pain (except thalamic pain), or brachial plexus injury, while patients with thalamic lesions had the least benefit. Thalamic DBS is a useful treatment option in selected patients with severe and medically refractory pain.
Learn More >Chronic pain is a leading cause of disability worldwide and its prevalence is likely to increase over the next decades. Treatment for chronic pain remains insufficient and therapeutical advances have not made comparable progress with that for many chronic disorders, thus amplifying the concern on the future burden of the disease. At the same time, and even after decades of intense research, the underlying pathophysiology of chronic pain remains minimally understood. We believe advancing our current understanding of chronic pain requires mechanistically explicit, hypothesis-driven, and clinically focused models. In this review we highlight some of the main findings over the last decades that have contributed to the present knowledge of brain mechanisms of chronic pain, and how such advances were possible due to a reverse translational research approach. We argue that this approach is essential in the chronic pain field, in order to generate new scientific hypotheses, probe physiological mechanisms, develop therapeutic strategies and translate findings back into promising human clinical trials.
Learn More >Peak alpha frequency (PAF) reduces during cutaneous pain, but no studies have investigated PAF during movement-related muscle pain. Whether high-pain sensitive (HPS) individuals exhibit a more pronounced PAF response to pain than low-pain sensitive (LPS) individuals is unclear. As a pain model, twenty-four participants received nerve growth factor injections into a wrist extensor muscle at Day0, Day2, and Day4. At Day4, a subgroup of twelve participants also undertook eccentric wrist exercise to induce additional pain. Pain numerical rating scale (NRS) scores and electroencephalography were recorded at Day0 (before injection), Day4, and Day6 for 3 minutes (eyes closed) with wrist at rest (Resting-state) and extension (Contraction-state). The average pain NRS scores in contraction-state across Days were used to divide participants into HPS (NRS-scores≥2) and LPS groups. PAF was calculated by frequency decomposition of electroencephalographic recordings. Compared with Day0, contraction NRS-scores only increased in HPS-group at Day4 and Day6 (P<0.001). PAF in Contraction-state decreased in both groups at Day6 compared with Day0 (P=0.011). Across days, HPS-group showed faster PAF than LPS-group during Resting-state and Contraction-state (P<0.04). Average pain NRS-scores across days during Contraction-states correlated with PAF at Day0 (P=0.012). Pain NRS-scores were associated with PAF during Contraction-state at Day4 and Day6 (P<0.05). Perspective: PAF was slowed during long-lasting movement-related pain in both groups, suggesting a widespread change in cortical excitability independent of the pain sensitivity. Moreover, HPS individuals showed faster PAF than LPS individuals during muscle pain, which may reflect a different cognitive, emotional, or attentional response to muscle pain among individuals.
Learn More >Neuroimaging and neuropsychological investigations have indicated that migraineurs exhibit frontal lobe-related cognitive impairment. We investigated whether orbitofrontal and dorsolateral functioning differed between individuals with episodic migraine (EM) and chronic migraine (CM), focusing on orbitofrontal dysfunction because it is implicated in migraine chronification and medication overuse headache (MOH) in migraineurs. This cross-sectional study recruited women with CM with/without MOH (CM + MOH, CM – MOH), EM, and control participants who were matched in terms of age and education. We conducted neuropsychological assessments of frontal lobe function via the Trail Making Test (TMT) A and B, the Wisconsin Card Sorting Test (WCST), and the Iowa Gambling Task (IGT). We enrolled 36 CM (19 CM + MOH, 17 CM – MOH), 30 EM, and 30 control participants. The CM patients performed significantly ( < 0.01) worse on the TMT A and B than the EM patients and the control participants. The WCST also revealed significant differences, with poorer performance in the CM patients versus the EM patients and the control participants. However, the net scores on the IGT did not significantly differ among the three groups. Our findings suggest that the CM patients exhibited frontal lobe dysfunction, and, particularly, dorsolateral dysfunction. However, we found no differences in frontal lobe function according to the presence or absence of MOH.
Learn More >Cisplatin, which is a chemotherapy drug listed on the World Health Organisation's List of Essential Medicines, commonly induces dose-limiting side effects including chemotherapy-induced peripheral neuropathy (CIPN) that has a major negative impact on quality of life in cancer survivors. Although adjuvant drugs including anticonvulsants and antidepressants are used for the relief of CIPN, analgesia is often unsatisfactory. Herein, we used a rat model of CIPN (cisplatin) to assess the effect of a glycine transporter 2 (GlyT2) inhibitor, relative to pregabalin, duloxetine, indomethacin and vehicle. Male Sprague-Dawley rats with cisplatin-induced mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws received oral bolus doses of the GlyT2 inhibitor (3-30 mg/kg), pregabalin (3-100 mg/kg), duloxetine (3-100 mg/kg), indomethacin (1-10 mg/kg) or vehicle. The GlyT2 inhibitor alleviated both mechanical allodynia and hyperalgesia in the bilateral hindpaws at a dose of 10 mg/kg, but not at higher or lower doses. Pregabalin and indomethacin induced dose-dependent relief of mechanical allodynia but duloxetine lacked efficacy. Pregabalin and duloxetine alleviated mechanical hyperalgesia in the bilateral hindpaws while indomethacin lacked efficacy. The mechanism underpinning pain relief induced by the GlyT2 inhibitor at 10 mg/kg is likely due to increased glycinergic inhibition in the lumbar spinal cord, although the bell-shaped dose-response curve warrants further translational considerations.
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