Role of sigma-1 receptors in paclitaxel-induced neuropathic pain in mice.
Sigma-1 (σ(1)) 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 σ(1) receptor knockout (σ(1)-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 σ(1) receptor antagonists that bind to the σ(1) receptor with high affinity and competitively. The responses to cold and mechanical stimuli were similar in WT and σ(1)-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 σ(1)-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 σ(1) receptor antagonists dose dependently reversed both types of paclitaxel-induced allodynia after they had fully developed. These results suggest that σ(1) receptors play a key role in paclitaxel-induced painful neuropathy.


CONCLUSIONS
Antagonists of the σ(1) 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.
Department of Pharmacology and Institute of Neuroscience, Faculty of Medicine, University of Granada, Granada, Spain.
Francisco Rafael
FR
Nieto
Cruz Miguel
CM
Cendán
Cristina
C
Sánchez-Fernández
Enrique José
EJ
Cobos
José Manuel
JM
Entrena
Miguel Angel
MA
Tejada
Daniel
D
Zamanillo
José Miguel
JM
Vela
José Manuel
JM
Baeyens
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D003080:Cold Temperature; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009294:Narcotics / Q000378:metabolism; D009437:Neuralgia / Q000139:chemically induced*; D017239:Paclitaxel; D010147:Pain Measurement / Q000187:drug effects; D010423:Pentazocine / Q000378:metabolism; D010812:Physical Stimulation; D010879:Piperazines / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology; D017480:Receptors, sigma / Q000819:agonists / Q000187:drug effects* / Q000235:genetics; D000097605:Sigma-1 Receptor
D000972:Antineoplastic Agents, Phytogenic; D009025:Morpholines; D009294:Narcotics; D017239:Paclitaxel; D010423:Pentazocine; D010879:Piperazines; D011720:Pyrazoles; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C093337:1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine; C576663:4-(2-((5-methyl-1-(2-naphthalenyl)-1H-pyrazol-3-yl)oxy)ethyl)morpholine