Prevention of cisplatin induced electrophysiological alterations in A-delta fibres by SR1A, a new sigma 1 antagonist.

R. GIRÓN MORENO1, N.A. PANIAGUA DE VEIZAGA1, J.M. VELA0,2, C. GOICOECHEA GARCÍA1, M.I. MARTÍN FONTELLES1. 1UNIVERSIDAD REY JUAN CARLOS, DEPARTAMENTO DE FARMACOLOGIA Y NUTRICION, 28922, Spain, 2LABORATORIOS DR. ESTEVE S.A., 08041, Spain

Antineoplastic drugs, such as cisplatin, cause neurotoxicity associated to disabling painful peripheral neuropathies. This impaired perception is referred by patients in ‘stocking-glove’, meaning that symptoms are localized at the distal parts of the lower and upper limbs. Cisplatin provokes clinical sensory abnormalities that are one of the major dose-limiting side effects. Cisplatin neuropathy predominantly involves large myelinated sensory nerve fibres and can become chronic, persisting for months or years after the termination of chemotherapy [Minerva Anestesiol. 72 (2006) 151-169] and could even induce irreversible damage. Sigma-1 receptors may serve as amplifiers for intracellular signal transduction in the CNS [Psychopharmacology 174 (2004) 301-319]. 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].

Our aim is to study the effect of S1RA, a recently described antagonist of the sigma-1 receptor [Br J Pharmacol (2012) in press], on the electrophysiological activity recorded on skin-saphenous nerve preparations obtained from control rats and from cisplatin treated animals.

The dose of cisplatin employed was 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 housed under standard conditions. Animals were injected with cisplatin, compound S1RA or both and were assigned to separate groups (n≥ 6). Neuronal activity was recorded in single A-delta fibres using gold-wire electrodes. A total of 32 A-delta units from 26 animals were studied, 8 units from control rats, 12 from cisplatin- (1 mg/kg) treated rats, 6 from animals treated with S1RA (64 mg/kg i.p.) and 6 from rats treated with cisplatin (1 mg/kg) and S1RA (64 mg/kg i.p.).

The analysed parameters were:

1. threshold response to an increasing pressure stimulation,

2. response to constant and maintained suprathreshold stimulation,

3. spontaneous discharges of action potentials.

S1RA did not modify these parameters whereas in preparations obtained from the cisplatin treated group of rats the electrophysiological activity was significantly enhanced in comparison with controls (thresholds: controls: 105 ± 9.7 mN, cisplatin group: 23.3 ± 3.9 mN, p<0.001; response to suprathreshold stimulation: controls: 16.1 ± 2.7 spikes, cisplatin group: 37.8 ± 4.2 spikes, p<0.001; spontaneous discharges: controls: 0.05 ± 0.02 spikes/s; cisplatin group: 0.21 ± 0.04 spikes/s, p<0.01. Results are expressed as mean ± S.E.M. values) and, what is really interesting, when cisplatin was administered together with the sigma antagonist, values recorded were similar to that obtained from control fibres (threshold: 56 ± 15.5 mN, p<0.05; response to suprathreshold stimulation: 15.9 ± 3.0 spikes, p<0.01; spontaneous discharges: 0.02 ± 0.01 spikes/s, p<0.001).

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.