Abstract
Sigma-1 (σ1) receptors play a role in different types of pain and in central sensitization mechanisms;
however, it is unknown whether they are involved in chemotherapy-induced neuropathic
pain. We compared the ability of paclitaxel to induce cold (acetone test) and mechanical
(electronic Von Frey test) allodynia in wild-type (WT) and σ1 receptor knockout (σ1-KO) mice. We also tested the effect on paclitaxel-induced painful neuropathy of BD-1063
(16–64 mg/kg, subcutaneously) and S1RA (32–128 mg/kg, subcutaneously), 2 selective
σ1 receptor antagonists that bind to the σ1 receptor with high affinity and competitively. The responses to cold and mechanical
stimuli were similar in WT and σ1-KO mice not treated with paclitaxel; however, treatment with paclitaxel (2 mg/kg,
intraperitoneally, once per day during 5 consecutive days) produced cold and mechanical
allodynia and an increase in spinal cord diphosphorylated extracellular signal-regulated
kinase (pERK) in WT but not in σ1-KO mice. The administration of BD-1063 or S1RA 30 minutes before each paclitaxel
dose prevented the development of cold and mechanical allodynia in WT mice. Moreover,
the acute administration of both σ1 receptor antagonists dose dependently reversed both types of paclitaxel-induced allodynia
after they had fully developed. These results suggest that σ1 receptors play a key role in paclitaxel-induced painful neuropathy.
Perspective
Antagonists of the σ1 receptor may have therapeutic value for the treatment and/or prevention of paclitaxel-induced
neuropathic pain. This possibility is especially interesting in the context of chemotherapy-induced
neuropathy, where the onset of nerve damage is predictable and preventive treatment
could be administered.
Key words
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References
- Different peripheral mechanisms mediate enhanced nociception in metabolic/toxic and traumatic painful peripheral neuropathies in the rat.Neuroscience. 2002; 111: 389-397
- Immunocytochemical localization of the sigma1 receptor in the adult rat central nervous system.Neuroscience. 2000; 97: 155-170
- Peripheral nerve damage associated with administration of taxanes in patients with cancer.Crit Rev Oncol Hematol. 2008; 66: 218-228
- A new animal model of vincristine-induced nociceptive peripheral neuropathy.Neurotoxicology. 2003; 24: 797-805
- Neuropathic pain: Diagnosis, pathophysiological mechanisms, and treatment.Lancet Neurol. 2010; 9: 807-819
- Pathophysiology and animal models of cancer-related painful peripheral neuropathy.Oncologist. 2010; 15: 9-12
- Evidence for a multi-site model of the rat brain sigma receptor.Eur J Pharmacol. 1989; 163: 309-318
- Interactions between 3,4-methylenedioxymethamphetamine and sigma1 receptors.Eur J Pharmacol. 2006; 553: 141-145
- Altered discharges of spinal wide dynamic range neurons and down-regulation of glutamate transporter expression in rats with paclitaxel-induced hyperalgesia.Neuroscience. 2006; 138: 329-338
- Antinociceptive effects of haloperidol and its metabolites in the formalin test in mice.Psychopharmacology (Berl). 2005; 182: 485-493
- Formalin-induced pain is reduced in σ1 receptor knockout mice.Eur J Pharmacol. 2005; 511: 73-74
- NMDA-receptor activation and nitroxidative regulation of the glutamatergic pathway during nociceptive processing.Pain. 2010; 149: 100-106
- Identification of MEK1 as a novel target for the treatment of neuropathic pain.Br J Pharmacol. 2003; 138: 751-756
- Phenytoin differentially modulates the affinity of agonist and antagonist ligands for σ1 receptors of guinea pig brain.Synapse. 2005; 55: 192-195
- Irreversible blockade of sigma-1 receptors by haloperidol and its metabolites in guinea pig brain and SH-SY5Y human neuroblastoma cells.J Neurochem. 2007; 102: 812-825
- Pharmacology and therapeutic potential of sigma1 receptor ligands.Curr Neuropharmacol. 2008; 6: 344-366
- Differences in the allosteric modulation by phenytoin of the binding properties of the σ1 ligands [3H](+)-pentazocine and [3H]NE-100.Synapse. 2006; 59: 152-161
- Synthesis and Biological Evaluation of the 1-Arylpyrazole Class of σ(1) Receptor Antagonists: Identification of 4-{2-[5-Methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy]ethyl}morpholine (S1RA, E-52862).J Med Chem. 2012 Jul 27; ([Epud ahead of print])
- Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury.Pain. 2009; 145: 294-303
- Role of protein kinase Cepsilon and protein kinase A in a model of paclitaxel-induced painful peripheral neuropathy in the rat.Neuroscience. 2001; 108: 507-515
- Taxol-induced sensory disturbance is characterized by preferential impairment of myelinated fiber function in cancer patients.Pain. 2004; 109: 132-142
- Central sensitization needs sigma receptors.Pain. 2009; 145: 269-270
- Recommendations for the pharmacological management of neuropathic pain: An overview and literature update.Mayo Clin Proc. 2010; 85: S3-S14
- Antagonism by haloperidol and its metabolites of mechanical hypersensitivity induced by intraplantar capsaicin in mice: Role of sigma-1 receptors.Psychopharmacology (Berl). 2009; 205: 21-33
- Sigma-1 receptors are essential for capsaicin-induced mechanical hypersensitivity: Studies with selective sigma-1 ligands and sigma-1 knockout mice.Pain. 2009; 143: 252-261
- Involvement of increased expression of transient receptor potential melastatin 8 in oxaliplatin-induced cold allodynia in mice.Neurosci Lett. 2009; 458: 93-95
- MAP kinase and pain.Brain Res Rev. 2009; 60: 135-148
- Neuropathic pain associated with non-surgical treatment of breast cancer.Pain. 2005; 118: 10-14
- Intrathecal treatment with sigma1 receptor antagonists reduces formalin-induced phosphorylation of NMDA receptor subunit 1 and the second phase of formalin test in mice.Br J Pharmacol. 2006; 148: 490-498
- Expression of the purported sigma (1) (σ1) receptor in the mammalian brain and its possible relevance in deficits induced by antagonism of the NMDA receptor complex as revealed using an antisense strategy.J Chem Neuroanat. 2000; 20: 375-387
- Central sensitization: A generator of pain hypersensitivity by central neural plasticity.J Pain. 2009; 10: 895-926
- The sigma-1 receptor modulates NMDA receptor synaptic transmision and plasticity via SK channels in rat hippocampus.J Physiol. 2007; 578: 143-157
- Characterization of two novel sigma receptor ligands: Antidystonic effects in rats suggest sigma receptor antagonism.Eur J Pharmacol. 1995; 280: 301-310
- The pharmacology of sigma-1 receptors.Pharmacol Ther. 2009; 124: 195-206
- Tetrodotoxin inhibits the development and expression of neuropathic pain induced by paclitaxel in mice.Pain. 2008; 137: 520-531
- Differential activation of MAPK in injured and uninjured DRG neurons following chronic constriction injury of the sciatic nerve in rats.Eur J Neurosci. 2004; 20: 2881-2895
- Chronic treatment-related pain in cancer survivors.Pain. 2011; 152: S84-S89
- Immunohistochemical localization of the sigma1 receptor in Schwann cells of rat sciatic nerve.Brain Res. 2004; 1007: 65-70
- Mechanisms underlying chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies.Curr Med Chem. 2008; 15: 3081-3094
- Intrathecal injection of the sigma (1) receptor antagonist BD1047 blocks both mechanical allodynia and increases in spinal NR1 expression during the induction phase of rodent neuropathic pain.Anesthesiology. 2008; 109: 879-889
- Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization.Br J Pharmacol. 2012; 166: 2289-2306
- Paclitaxel- and vincristine-evoked painful peripheral neuropathies: Loss of epidermal innervation and activation of Langerhans cells.Exp Neurol. 2006; 201: 507-514
- Paclitaxel-induced neuropathic hypersensitivity in mice: Responses in 10 inbred mouse strains.Life Sci. 2004; 74: 2593-2604
- A conditional deletion of the NR1 subunit of the NMDA receptor in adult spinal cord dorsal horn reduces NMDA currents and injury-induced pain.J Neurosci. 2003; 23: 5031-5040
- Neurologic complications of cancer chemotherapy.Semin Oncol. 2006; 33: 324-332
- Spinal glial glutamate transporters down regulate in rats with taxol-induced hyperalgesia.Neurosci Lett. 2005; 386: 18-22
- Scheduling of taxanes: A review.Curr Clin Pharmacol. 2010; 5: 226-231
- Central sensitization: Implications for the diagnosis and treatment of pain.Pain. 2011; 152: S2-S15
- Chemotherapy-evoked neuropathic pain: Abnormal spontaneous discharge in A-fiber and C-fiber primary afferent neurons and its suppression by acetyl-L-carnitine.Pain. 2008; 135: 262-270
- Characterization of oxaliplatin-induced chronic painful peripheral neuropathy in the rat and comparison with the neuropathy induced by paclitaxel.Neuroscience. 2012; 203: 194-206
- Pregabalin reduces muscle and cutaneous hyperalgesia in two models of chronic muscle pain in rats.J Pain. 2007; 8: 422-429
- Evidence that spinal astrocytes but not microglia contribute to the pathogenesis of paclitaxel-induced painful neuropathy.J Pain. 2012; 13: 293-303
- The response of spinal microglia to chemotherapy-evoked painful peripheral neuropathies is distinct from that evoked by traumatic nerve injuries.Neuroscience. 2011; 176: 447-454
- Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy.Exp Neurol. 2011; 232: 154-161
- ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model.Pain. 2005; 114: 149-159
Article info
Publication history
Published online: October 15, 2012
Accepted:
August 20,
2012
Received in revised form:
August 4,
2012
Received:
March 9,
2012
Footnotes
F. R. Nieto and C. Sánchez-Fernández were supported by FPU grants from the Spanish Ministerio de Educación y Ciencia (MEC), and E. J. Cobos and C. M. Cendán by the Research Program of the University of Granada. This research was done in partial fulfillment of the requirements for the doctoral thesis of F. R. Nieto. This study was partially supported by grant SAF 2006-06122 (MEC), grant CTS 109 from the Junta de Andalucía, European Union (FEDER funds), a grant from Laboratorios Esteve, and a grant from The Centre for Industrial Technological Development (Spanish Government) (Genius Pharma project).
The authors declare no conflicts of interest.
Identification
Copyright
© 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.
