Limits...
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

Paclitaxel induces acute mechanical allodynia and reduces burrowing activities. (A) and (B): Mechanical thresholds of withdrawal responses in rats before (baseline) and at different time points after i.v. injection of paclitaxel at 2 mg/kg (A), 5 mg/kg (B), or vehicle are plotted. (C) and (D): Burrowing activities in rats at different time points after i.v. injection of paclitaxel at 2 mg/kg (C), 5 mg/kg (D), or vehicle are normalized to burrowing activities collected before the i.v. injection (baseline). Comparisons between baseline and at each time point are indicated with ^ for the paclitaxel group. Comparisons between the vehicle group and the paclitaxel group at each time point are labeled with #. One symbol: P < 0.05; Two symbols: P < 0.01; Three symbols: P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4363343&req=5

Fig1: Paclitaxel induces acute mechanical allodynia and reduces burrowing activities. (A) and (B): Mechanical thresholds of withdrawal responses in rats before (baseline) and at different time points after i.v. injection of paclitaxel at 2 mg/kg (A), 5 mg/kg (B), or vehicle are plotted. (C) and (D): Burrowing activities in rats at different time points after i.v. injection of paclitaxel at 2 mg/kg (C), 5 mg/kg (D), or vehicle are normalized to burrowing activities collected before the i.v. injection (baseline). Comparisons between baseline and at each time point are indicated with ^ for the paclitaxel group. Comparisons between the vehicle group and the paclitaxel group at each time point are labeled with #. One symbol: P < 0.05; Two symbols: P < 0.01; Three symbols: P < 0.001.

Mentions: To determine whether paclitaxel induces acute pain in animals, nociceptive behaviors in rats were examined after the rats were treated with paclitaxel or saline. Paclitaxel (dose: 2 mg/kg; volume: 1 ml; duration of the injection: 1 min) was given to rats via the tail vein to simulate intravenous (i.v.) administration of taxol used in the clinic. Vehicle control (1 ml) was injected into the rats in the same fashion in the control group. A single i.v. injection of taxol reduced thresholds of hind paw withdrawal responses to mechanical stimuli, which occurred within 2 hrs and peaked at 4 hrs but resolved within 24 hrs after taxol injection (Figure 1A). Meanwhile, thresholds of hind paw withdrawal responses to mechanical stimuli in rats receiving vehicle (control group) remained unchanged. This is in agreement with a previous report [32] showing that a single intraperitoneal injection (i.p.) of paclitaxel (1 mg/kg) in rats induces acute mechanical allodynia between 1 and 6 hrs after paclitaxel treatment. Furthermore, we also determined the changes of mechanical thresholds following i.v. paclitaxel injection at a higher dose (5 mg/kg). Mechanical allodynia was observed within 1 hr, peaked between 4 to 6 hrs, lasted more than 48 hrs, and ended before 72 hrs after paclitaxel injection (Figure 1B), which lasts significantly longer than that induced by paclitaxel at 2 mg/kg (Figure 1A). At the same time period, mechanical thresholds in rats receiving vehicle were not significantly altered. These data indicate that paclitaxel induces acute mechanical allodynia in a dose-dependent manner.Figure 1


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)

Paclitaxel induces acute mechanical allodynia and reduces burrowing activities. (A) and (B): Mechanical thresholds of withdrawal responses in rats before (baseline) and at different time points after i.v. injection of paclitaxel at 2 mg/kg (A), 5 mg/kg (B), or vehicle are plotted. (C) and (D): Burrowing activities in rats at different time points after i.v. injection of paclitaxel at 2 mg/kg (C), 5 mg/kg (D), or vehicle are normalized to burrowing activities collected before the i.v. injection (baseline). Comparisons between baseline and at each time point are indicated with ^ for the paclitaxel group. Comparisons between the vehicle group and the paclitaxel group at each time point are labeled with #. One symbol: P < 0.05; Two symbols: P < 0.01; Three symbols: P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4363343&req=5

Fig1: Paclitaxel induces acute mechanical allodynia and reduces burrowing activities. (A) and (B): Mechanical thresholds of withdrawal responses in rats before (baseline) and at different time points after i.v. injection of paclitaxel at 2 mg/kg (A), 5 mg/kg (B), or vehicle are plotted. (C) and (D): Burrowing activities in rats at different time points after i.v. injection of paclitaxel at 2 mg/kg (C), 5 mg/kg (D), or vehicle are normalized to burrowing activities collected before the i.v. injection (baseline). Comparisons between baseline and at each time point are indicated with ^ for the paclitaxel group. Comparisons between the vehicle group and the paclitaxel group at each time point are labeled with #. One symbol: P < 0.05; Two symbols: P < 0.01; Three symbols: P < 0.001.
Mentions: To determine whether paclitaxel induces acute pain in animals, nociceptive behaviors in rats were examined after the rats were treated with paclitaxel or saline. Paclitaxel (dose: 2 mg/kg; volume: 1 ml; duration of the injection: 1 min) was given to rats via the tail vein to simulate intravenous (i.v.) administration of taxol used in the clinic. Vehicle control (1 ml) was injected into the rats in the same fashion in the control group. A single i.v. injection of taxol reduced thresholds of hind paw withdrawal responses to mechanical stimuli, which occurred within 2 hrs and peaked at 4 hrs but resolved within 24 hrs after taxol injection (Figure 1A). Meanwhile, thresholds of hind paw withdrawal responses to mechanical stimuli in rats receiving vehicle (control group) remained unchanged. This is in agreement with a previous report [32] showing that a single intraperitoneal injection (i.p.) of paclitaxel (1 mg/kg) in rats induces acute mechanical allodynia between 1 and 6 hrs after paclitaxel treatment. Furthermore, we also determined the changes of mechanical thresholds following i.v. paclitaxel injection at a higher dose (5 mg/kg). Mechanical allodynia was observed within 1 hr, peaked between 4 to 6 hrs, lasted more than 48 hrs, and ended before 72 hrs after paclitaxel injection (Figure 1B), which lasts significantly longer than that induced by paclitaxel at 2 mg/kg (Figure 1A). At the same time period, mechanical thresholds in rats receiving vehicle were not significantly altered. These data indicate that paclitaxel induces acute mechanical allodynia in a dose-dependent manner.Figure 1

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