The role of a sigma-1 (s 1 ) antagonist in the sensory peripheral neuropathy induced by cisplatin in rats.

N A PANIAGUA DE VEIZAGA1, M R GIRON MORENO1, C GOICOECHEA GARCIA1, J M VELA2, M I MARTIN FONTELLES1. 1Departamento de Farmacología y Nutrición, Universidad Rey Juan Carlos, 28922, Spain, 2Laboratorios Dr Esteve S.A., 08041, Spain

Some drugs used in chemotherapy, such as cisplatin, cause neurotoxicity associated to disabling painful peripheral neuropathies. This drug provokes clinical pain and sensory abnormalities that are one of the major dose-limiting side effects, being the main symptoms numbness and tingling, mechanical allodynia, weakness and on-going burning pain and could even induce irreversible damage. Sigma-1 receptors (Sig-1R) may serve as amplifiers for intracellular signal transduction in the CNS [Psychopharmacology 174 (2004) 301-319] and it has been demonstrated that they play an important role in pain processing [Eur J Pharmacol. 511 (2005) 73-74] and their selective blockade in the spinal cord reduced pain behaviours in some neuropathic pain rodents [Br J Pharmacol. 154 (2008) 1125-1134, Anaesthesiology 109 (2008) 879-889].

The aim of this study was to evaluate the effect of S1RA, a recently described antagonist of the sigma-1 receptor [Br J Pharmacol (2012) in press], on neuropathic signs induced in rats by i.p. administration of repeated doses of cisplatin.

The doses of cisplatin employed were selected in order to avoid a high degree of toxicity and to approach our experimental conditions to those that are acceptable in the therapeutic use.

Experiments were performed using male Wistar rats weighing (250–275 g) that were obtained from Harlan Laboratories (Barcelona, Spain) and housed under standard conditions. Animals were injected with cisplatin, compound S1RA or both and were assigned to separated groups (n≥ 8) to evaluate behavioural changes: plantar test for thermal hyperalgesia; von Frey test for mechanical allodynia, and spontaneous locomotor activity and body weigth to evaluate welfare.

Cisplatin (1 mg/kg, i.p, weekly) induced tactile allodynia in the 100% of the animals that was maximal at the 5th week after the first injection of the antineoplastic. This sign was observed as a drop of 33.5±2.4% in the von Frey filament threshold response. In contrast, no significant signs of thermal hyperalgesia were detected in the plantar test. The acute administration of S1RA (64 mg/kg i.p.) reversed the mechanical allodynia to basal values in the von Frey test. In the plantar test the compound induced an increase of 37±6.4% of the basal nociceptive threshold value.

Interestingly, the results of the von Frey test showed that the co-administration of cisplatin (1 mg/kg, i.p.) and S1RA (25 mg/kg, i.p. BID) inhibited the development of mechanical allodynia induced by chronic treatment of cisplatin; values, at the end of treatment (5th week) were similar to controls and even two weeks later (7th week) remained unchanged which demonstrated that the development of the damage has been prevented. The remaining parameters (heat hyperalgesia, spontaneous locomotor activity and weight) were not significantly modified.

These results suggest that S1RA may be considered as an interesting option to reduce or prevent the development neuropathic sings induced by cisplatin.

All experimental protocols were approved by our Ethical Committee according with the EC regulation for care and use of experimental animals (86/609/EEC).

We acknowledge Ivan Álvarez for his technical support.

Supported by Laboratorios Dr. Esteve S.A.