Peripheral neuropathy is dose limiting in paclitaxel cancer chemotherapy and can result in both acute pain during treatment and chronic persistent pain in cancer survivors. The hypothesis tested was that paclitaxel produces these adverse effects at least in part by sensitizing transient receptor potential vanilloid subtype 1 (TRPV1) through Toll-like receptor 4 (TLR4) signaling. The data show that paclitaxelinduced behavioral hypersensitivity is prevented and reversed by spinal administration of a TRPV1 antagonist. The number of TRPV1 ϩ neurons is increased in the dorsal root ganglia (DRG) in paclitaxel-treated rats and is colocalized with TLR4 in rat and human DRG neurons. Cotreatment of rats with lipopolysaccharide from the photosynthetic bacterium Rhodobacter sphaeroides (LPS-RS), a TLR4 inhibitor, prevents the increase in numbers of TRPV1 ϩ neurons by paclitaxel treatment. Perfusion of paclitaxel or the archetypal TLR4 agonist LPS activated both rat DRG and spinal neurons directly and produced acute sensitization of TRPV1 in both groups of cells via a TLR4-mediated mechanism. Paclitaxel and LPS sensitize TRPV1 in HEK293 cells stably expressing human TLR4 and transiently expressing human TRPV1. These physiological effects also are prevented by LPS-RS. Finally, paclitaxel activates and sensitizes TRPV1 responses directly in dissociated human DRG neurons. In summary, TLR4 was activated by paclitaxel and led to sensitization of TRPV1. This mechanism could contribute to paclitaxel-induced acute pain and chronic painful neuropathy.

Here it is shown that paclitaxel induced neuropathy is associated with the development of spontaneous activity (SA) and hyperexcitability in DRG neurons that is paralleled by increased expression of low-voltage-activated calcium channels (T-type; Ca v 3.2). The percentage of DRG neurons showing SA and the overall mean rate of SA were significantly higher at day 7 of paclitaxel treatment than in rats receiving vehicle. Ca v 3.2 expression was increased in L4-6 DRG and spinal cord segments in paclitaxel-treated rats, localized to small calcitonin gene-related peptide expressing and isolectin B4 expressing DRG neurons and to glial fibrillary acidic proteinpositive spinal cord cells. Ca v 3.2 expression was also co-localized with toll-like receptor 4 (TLR4) in both the DRG and dorsal horn. T-type current amplitudes and density were increased at day 7 after paclitaxel treatment. Perfusion of the TLR4 agonist lipopolysaccharide (LPS) directly activated DRG neurons, whereas this was prevented by pretreatment with the specific T-type calcium channel inhibitor ML218 hydrochloride. Paclitaxel-induced behavioral hypersensitivity to mechanical stimuli in rats was prevented but not reversed by spinal administration of ML218 hydrochloride or intravenous (i.v.) injection of the TLR4 antagonist TAK242. Paclitaxel induced inward current and action potential discharges in cultured human DRGs neurons and this was blocked by ML218 hydrochloride pretreatment. Furthermore, ML218 hydrochloride decreased

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect experienced by cancer patients receiving treatment with paclitaxel. The voltage-gated sodium channel 1.7 (Na1.7) plays an important role in multiple preclinical models of neuropathic pain and in inherited human pain phenotypes, and its gene expression is increased in dorsal root ganglia (DRGs) of paclitaxel-treated rats. Hence, the potential of change in the expression and function of Na1.7 protein in DRGs from male rats with paclitaxel-related CIPN and from male and female humans with cancer-related neuropathic pain was tested here. Double immunofluorescence in CIPN rats showed that Na1.7 was upregulated in small DRG neuron somata, especially those also expressing calcitonin gene-related peptide (CGRP), and in central processes of these cells in the superficial spinal dorsal horn. Whole-cell patch-clamp recordings in rat DRG neurons revealed that paclitaxel induced an enhancement of ProTx II (a selective Na1.7 channel blocker)-sensitive sodium currents. Bath-applied ProTx II suppressed spontaneous action potentials in DRG neurons occurring in rats with CIPN, while intrathecal injection of ProTx II significantly attenuated behavioral signs of CIPN. Complementarily, DRG neurons isolated from segments where patients had a history of neuropathic pain also showed electrophysiological and immunofluorescence results indicating an increased expression of Na1.7 associated with spontaneous activity. Na1.7 was also colocalized in human cells expressing transient receptor potential vanilloid 1 and CGRP. Furthermore, ProTx II decreased firing frequency in human DRGs with spontaneous action potentials. This study suggests that Na1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain. This work demonstrates that the expression and function of the voltage-gated sodium channel Na1.7 are increased in a preclinical model of chemotherapy-induced peripheral neuropathy (CIPN), the most common treatment-limiting side effect of all the most common anticancer therapies. This is key as gain-of-function mutations in human Na1.7 recapitulate both the distribution and pain percept as shown by CIPN patients. This work also shows that Na1.7 is increased in human DRG neurons only in dermatomes where patients are experiencing acquired neuropathic pain symptoms. This work therefore has major translational impact, indicating an important novel therapeutic avenue for neuropathic pain as a class.

Ongoing pain has been linked to ongoing activity (OA) in human C-fiber nociceptors, but rodent models of pain-related OA have concentrated on allodynia rather than ongoing pain, and on OA generated in non-nociceptive Aβ fibers rather than C-fiber nociceptors. Little is known about how ongoing pain or nociceptor OA is generated. To define neurophysiological alterations underlying nociceptor OA, we have used isolated dorsal root ganglion neurons that continue to generate OA after removal from animals displaying ongoing pain. We subclassify OA as either spontaneous activity generated solely by alterations intrinsic to the active neuron or as extrinsically driven OA. Both types of OA were implicated previously in nociceptors in vivo and after isolation following spinal cord injury, which produces chronic ongoing pain. Using novel automated algorithms to analyze irregular changes in membrane potential, we have found, in a distinctive, nonaccommodating type of probable nociceptor, induction by spinal cord injury of 3 alterations that promote OA: (1) prolonged depolarization of resting membrane potential, (2) a hyperpolarizing shift in the voltage threshold for action potential generation, and (3) an increase in the incidence of large depolarizing spontaneous fluctuations (DSFs). Can DSFs also be enhanced acutely to promote OA in neurons from uninjured animals? A low dose of serotonin failed to change resting membrane potential but lowered action potential threshold. When combined with artificial depolarization to model inflammation, serotonin also strongly potentiated DSFs and OA. These findings reveal nociceptor specializations for generating OA that may promote ongoing pain in chronic and acute conditions.

The lifetime risk of suicide and suicide attempt in patients with schizophrenia are 5% and 25%-50%, respectively. The current meta-analysis aims to determine risk factors associated with suicidality in subjects with schizophrenia. We searched Pubmed, Web of Science, EMBASE, and the reference lists of included studies. Inclusion criteria were met if an article reported a dichotomous sample of patients with schizophrenia with suicidal ideation, attempted suicide, or suicide compared to patients without. We also performed a cohort study meta-analysis as a supplemental analysis. A total of 96 studies with 80488 participants were included in our analysis. Depressive symptoms (P < .0001), Positive and Negative Symptom Scale (PANSS) general score (P < .0001) and number of psychiatric hospitalizations (P < .0001) were higher in patients with suicide ideation. History of alcohol use (P = .0001), family history of psychiatric illness (P < .0001), physical comorbidity (P < .0001), history of depression (P < .0001), family history of suicide (P < .0001), history of drug use (P = .0024), history of tobacco use (P = .0034), being white (P = .0022), and depressive symptoms (P < .0001) were the most consistent variables associated with suicide attempts. The first two were also significant in the cohort meta-analysis. Being male (P = .0005), history of attempted suicide (P < .0001), younger age (P = .0266), higher intelligence quotient (P < .0001), poor adherence to treatment (P < .0001), and hopelessness (P < .0001) were the most consistently associated with suicide. The first three were also significant in the cohort meta-analysis. Our findings may help with future development of preventive strategies to combat suicide. Future studies may combine the above-mentioned variables by using multivariate predictive analysis techniques to objectively stratify suicidality in schizophrenia.