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Paclitaxel induces acute pain via directly activating toll like receptor 4.

Yan X, Maixner DW, Yadav R, Gao M, Li P, Bartlett MG, Weng HR - Mol Pain (2015)

Bottom Line: Paclitaxel, a powerful anti-neoplastic drug, often causes pathological pain, which significantly reduces the quality of life in patients.Through activating TLR4, paclitaxel increases glutamatergic synaptic activities and reduces glial glutamate transporter activities in the dorsal horn.The cellular and molecular signaling pathways revealed in this study could provide rationales for the development of analgesics and management strategies for P-APS in patients.

View Article: PubMed Central - PubMed

ABSTRACT
Paclitaxel, a powerful anti-neoplastic drug, often causes pathological pain, which significantly reduces the quality of life in patients. Paclitaxel-induced pain includes pain that occurs immediately after paclitaxel treatment (paclitaxel-associated acute pain syndrome, P-APS) and pain that persists for weeks to years after cessation of paclitaxel treatment (paclitaxel induced chronic neuropathic pain). Mechanisms underlying P-APS remain unknown. In this study, we found that paclitaxel causes acute pain in rodents in a dose-dependent manner. The paclitaxel-induced acute pain occurs within 2 hrs after a single intravenous injection of paclitaxel. This is accompanied by low levels of paclitaxel penetrating into the cerebral spinal fluid and spinal dorsal horn. We demonstrated that an intrathecal injection of paclitaxel induces mechanical allodynia in a dose-dependent manner. Paclitaxel causes activation of toll like receptor 4 (TLR4) in the spinal dorsal horn and dorsal root ganglions. Through activating TLR4, paclitaxel increases glutamatergic synaptic activities and reduces glial glutamate transporter activities in the dorsal horn. Activations of TLR4 are necessary in the genesis of paclitaxel-induced acute pain. The cellular and molecular signaling pathways revealed in this study could provide rationales for the development of analgesics and management strategies for P-APS in patients.

No MeSH data available.


Related in: MedlinePlus

TLR4 in the spinal dorsal horn and dorsal root ganglions are activated following intravenous or intrathecal injection of paclitaxel. Expression of phosphorylated TLR4 (p-TLR4) and total TLR4 (t-TLR4) in the spinal dorsal horn and dorsal root ganglions of L4-L5 spinal segments 4 hrs after i.v. injection of taxol (2 mg/kg) or vehicle are shown in (A). Expression of phosphorylated TLR4 (p-TLR4) and total TLR4 (t-TLR4) in the spinal dorsal horn and dorsal root ganglions of L4-L5 spinal segments 1 hr after intrathecal injection of taxol (20 ng) or vehicle are shown in (B). Number of animals included in each group for the analysis is indicated in each bar. *P < 0.05; **P < 0.01; ***P < 0.001.
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Fig3: TLR4 in the spinal dorsal horn and dorsal root ganglions are activated following intravenous or intrathecal injection of paclitaxel. Expression of phosphorylated TLR4 (p-TLR4) and total TLR4 (t-TLR4) in the spinal dorsal horn and dorsal root ganglions of L4-L5 spinal segments 4 hrs after i.v. injection of taxol (2 mg/kg) or vehicle are shown in (A). Expression of phosphorylated TLR4 (p-TLR4) and total TLR4 (t-TLR4) in the spinal dorsal horn and dorsal root ganglions of L4-L5 spinal segments 1 hr after intrathecal injection of taxol (20 ng) or vehicle are shown in (B). Number of animals included in each group for the analysis is indicated in each bar. *P < 0.05; **P < 0.01; ***P < 0.001.

Mentions: It is known that paclitaxel has LPS-mimetic activity causing activation of TLR4 [7,35,36], and activation of TLR4 causes TLR4 tyrosine phosphorylation (p-TLR4) [37,38]. Using Western blot, we determined if TLR4 receptors are activated following paclitaxel i.v. injection by examining p-TLR4 levels in the spinal dorsal horn and dorsal root ganglions at the L4-L5 segments. We found that in comparison with rats treated with i.v. vehicle injection, expressions of p-TLR4 in the spinal dorsal horn and dorsal root ganglions were increased, whereas total TLR4 (t-TLR4) remained unchanged 4 hrs after i.v. injection of taxol (2 mg/kg) (Figure 3). We then examined levels of p-TLR4 in the spinal dorsal horn and dorsal root ganglions at the L4-L5 spinal segments in rats 1 hr after paclitaxel (20 ng) or vehicle (in a volume of 20 μl) was injected into the intrathecal space through lumbar puncture. We found that in comparison with rats receiving vehicle treatment, levels of p-TLR4 in the spinal dorsal horn and dorsal root ganglions were increased in rats treated with intrathecal (i.t.) injection of paclitaxel. At the same time, no difference of t-TLR4 levels was found between paclitaxel treated and vehicle-treated groups. These data indicate that TLR4 at the spinal dorsal horn and dorsal root ganglions is activated following i.v. or i.t. injection of paclitaxel.Figure 3


Paclitaxel induces acute pain via directly activating toll like receptor 4.

Yan X, Maixner DW, Yadav R, Gao M, Li P, Bartlett MG, Weng HR - Mol Pain (2015)

TLR4 in the spinal dorsal horn and dorsal root ganglions are activated following intravenous or intrathecal injection of paclitaxel. Expression of phosphorylated TLR4 (p-TLR4) and total TLR4 (t-TLR4) in the spinal dorsal horn and dorsal root ganglions of L4-L5 spinal segments 4 hrs after i.v. injection of taxol (2 mg/kg) or vehicle are shown in (A). Expression of phosphorylated TLR4 (p-TLR4) and total TLR4 (t-TLR4) in the spinal dorsal horn and dorsal root ganglions of L4-L5 spinal segments 1 hr after intrathecal injection of taxol (20 ng) or vehicle are shown in (B). Number of animals included in each group for the analysis is indicated in each bar. *P < 0.05; **P < 0.01; ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Fig3: TLR4 in the spinal dorsal horn and dorsal root ganglions are activated following intravenous or intrathecal injection of paclitaxel. Expression of phosphorylated TLR4 (p-TLR4) and total TLR4 (t-TLR4) in the spinal dorsal horn and dorsal root ganglions of L4-L5 spinal segments 4 hrs after i.v. injection of taxol (2 mg/kg) or vehicle are shown in (A). Expression of phosphorylated TLR4 (p-TLR4) and total TLR4 (t-TLR4) in the spinal dorsal horn and dorsal root ganglions of L4-L5 spinal segments 1 hr after intrathecal injection of taxol (20 ng) or vehicle are shown in (B). Number of animals included in each group for the analysis is indicated in each bar. *P < 0.05; **P < 0.01; ***P < 0.001.
Mentions: It is known that paclitaxel has LPS-mimetic activity causing activation of TLR4 [7,35,36], and activation of TLR4 causes TLR4 tyrosine phosphorylation (p-TLR4) [37,38]. Using Western blot, we determined if TLR4 receptors are activated following paclitaxel i.v. injection by examining p-TLR4 levels in the spinal dorsal horn and dorsal root ganglions at the L4-L5 segments. We found that in comparison with rats treated with i.v. vehicle injection, expressions of p-TLR4 in the spinal dorsal horn and dorsal root ganglions were increased, whereas total TLR4 (t-TLR4) remained unchanged 4 hrs after i.v. injection of taxol (2 mg/kg) (Figure 3). We then examined levels of p-TLR4 in the spinal dorsal horn and dorsal root ganglions at the L4-L5 spinal segments in rats 1 hr after paclitaxel (20 ng) or vehicle (in a volume of 20 μl) was injected into the intrathecal space through lumbar puncture. We found that in comparison with rats receiving vehicle treatment, levels of p-TLR4 in the spinal dorsal horn and dorsal root ganglions were increased in rats treated with intrathecal (i.t.) injection of paclitaxel. At the same time, no difference of t-TLR4 levels was found between paclitaxel treated and vehicle-treated groups. These data indicate that TLR4 at the spinal dorsal horn and dorsal root ganglions is activated following i.v. or i.t. injection of paclitaxel.Figure 3

Bottom Line: Paclitaxel, a powerful anti-neoplastic drug, often causes pathological pain, which significantly reduces the quality of life in patients.Through activating TLR4, paclitaxel increases glutamatergic synaptic activities and reduces glial glutamate transporter activities in the dorsal horn.The cellular and molecular signaling pathways revealed in this study could provide rationales for the development of analgesics and management strategies for P-APS in patients.

View Article: PubMed Central - PubMed

ABSTRACT
Paclitaxel, a powerful anti-neoplastic drug, often causes pathological pain, which significantly reduces the quality of life in patients. Paclitaxel-induced pain includes pain that occurs immediately after paclitaxel treatment (paclitaxel-associated acute pain syndrome, P-APS) and pain that persists for weeks to years after cessation of paclitaxel treatment (paclitaxel induced chronic neuropathic pain). Mechanisms underlying P-APS remain unknown. In this study, we found that paclitaxel causes acute pain in rodents in a dose-dependent manner. The paclitaxel-induced acute pain occurs within 2 hrs after a single intravenous injection of paclitaxel. This is accompanied by low levels of paclitaxel penetrating into the cerebral spinal fluid and spinal dorsal horn. We demonstrated that an intrathecal injection of paclitaxel induces mechanical allodynia in a dose-dependent manner. Paclitaxel causes activation of toll like receptor 4 (TLR4) in the spinal dorsal horn and dorsal root ganglions. Through activating TLR4, paclitaxel increases glutamatergic synaptic activities and reduces glial glutamate transporter activities in the dorsal horn. Activations of TLR4 are necessary in the genesis of paclitaxel-induced acute pain. The cellular and molecular signaling pathways revealed in this study could provide rationales for the development of analgesics and management strategies for P-APS in patients.

No MeSH data available.


Related in: MedlinePlus