Antinociceptive efficacy of lacosamide in a rat model for painful diabetic neuropathy

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Abstract

Lacosamide was tested in the streptozotocin rat model of diabetic neuropathic pain in comparison to drugs which are commonly used in the treatment of diabetic neuropathic pain, i.e. antidepressants and anticonvulsants. In diabetic rats, lacosamide attenuated cold (10, 30 mg/kg, i.p.), warm (3, 10, 30 mg/kg, i.p.) and mechanical allodynia (30 mg/kg, i.p.). Streptozotocin-induced thermal and mechanical hyperalgesia were reduced by lacosamide at doses of 10 and 30 mg/kg, i.p. Morphine (3 mg/kg) showed similar efficacy on allodynia and hyperalgesia. Amitriptyline (10 mg/kg), venlafaxine (15 mg/kg), levetiracetam (180 mg/kg) and pregabalin (100 mg/kg) exhibited significant effects on thermal allodynia and mechanical hyperalgesia. Only treatment with amitriptyline (30 mg/kg, i.p.) produced full reversal of thermal allodynia comparable to lacosamide. Lamotrigine (45 mg/kg, i.p.) had no effect on both behavioral readouts. Lacosamide's potency and efficacy in reversing pain behavior might be due to its new, yet unknown mechanism of action.

Introduction

The most common precipitating cause of neuropathic pain is diabetes particularly where blood glucose control is poor (Morley et al., 1984). Approximately 20–24% of diabetes patients experience neuropathic pain (Schmader, 2002). Diabetic neuropathic pain can occur either spontaneously, as a result of exposure to normally mildly painful stimuli (i.e. hyperalgesia), or to stimuli that are not normally perceived as being painful (i.e. allodynia) (Brown and Asbury, 1984).

The cause of painful diabetic neuropathy, like other neuropathic pain states, is still unclear (Calcutt, 2002, Sommer, 2003). However, behavioral and physiological studies have revealed indices of sensory dysfunction in animal models of diabetes that include hyperalgesia to mechanical and noxious chemical stimuli and allodynia to light touch.

Currently, the three major classes of drugs recognized as being effective in neuropathic pain treatment are antidepressants, anticonvulsants and opioids (Galer, 1995, McQuay et al., 1996, Sindrup and Jensen, 1999). There remains a clear unmet medical need for drugs that provide greater efficacy/responder rates, with reduced side effects commonly experienced with current therapies.

A number of agents that are effective in the treatment of patients suffering from diabetic neuropathic pain have been shown to partially alleviate mechanical hyperalgesia in the streptozotocin-induced diabetes animal model of painful diabetic neuropathy (Courteix et al., 1994), the most commonly used model in the field of diabetic pain research (Fox et al., 1999).

Lacosamide (R-2-acetamido-N-benzyl-3-methoxypropionamide, SPM 927, also formerly called harkoseride or ADD 234037) has been shown to be active in animal models for neuropathic and inflammatory pain at doses of 8 mg/kg to 40 mg/kg i.p. (Morrow et al., 2001, Stohr et al., 2006). In addition, oral lacosamide produced analgesia in an open label study of 25 adult human subjects with resistant neuropathic pain (McCleane et al., 2003).

In the present study we examined the effects of lacosamide in comparison to morphine, amitriptyline, venlafaxine, lamotrigine, levetiracetam and pregabalin on allodynia and hyperalgesia in the streptozotocin-induced rat model of diabetic neuropathic pain. All doses of the drugs were chosen according their potency in published pain models. In a set of preliminary control experiments the best time points after streptozotocin-treatment for measurement of allodynia and hyperalgesia were identified. To have a broad description of pain behavior in the streptozotocin model we established assessment of five different pain qualities, i.e. cold, warm and tactile allodynia as well as thermal and mechanical hyperalgesia.

Section snippets

Animals

All experiments were carried out in accordance with the European Community guidelines for the use of experimental animals, and in accordance to the institutional guidelines of Neurofit and were approved by the responsible institutional committee.

Six week old, male Sprague–Dawley rats (body weight 200–225 g, Janvier, France) were group-housed (n = 5 per cage) in a room with controlled temperature (21–22 °C), and a reversed light–dark cycle (12 h/12 h), and they had access to food and water ad

Development of body weight and blood glucose levels in streptozotocin-treated rats

The streptozotocin-treated animals had 17% less body weight than the control rats on day 10 and 24% less on day 20 (Fig. 1). The average blood glucose levels of the streptozotocin-treated animals were 515 mg/dl on day 10 and 551 mg/dl on day 20 compared to 116 mg/dl of the control animals (Fig. 1). The general health was monitored strictly and even though the diabetic rats had a slightly reduced body weight all animals demonstrated normal behavior during the entire study.

Behavioral tests in naïve animals

The non-diabetic

Discussion

The results of the current study have confirmed previous findings (Courteix et al., 1998) that hyperglycaemia induced by diabetes in rats alters pain sensitivity by producing both allodynia and hyperalgesia. Although one tries to mimic the symptoms and etiology associated with neuropathic pain in patients, it is difficult to assess and thus predict the clinical efficacy of novel drugs in rat models. By assessing as many primary preclinical end points as possible, even though they might not be

Acknowledgements

The authors gratefully acknowledge Emile Andriambelson and Julien Bindler for their support in performing the animal studies.

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