Neuropharmacology and AnalgesiaOral pregabalin reverses cold allodynia in two distinct models of peripheral neuropathic pain
Introduction
Chronic neuropathic pain may arise as a consequence of peripheral nerve injury and is an area of major unmet medical needs, due to limitations of analgesic efficacy and dose limiting safety issues of current therapies. Consequently, the search for more efficacious analgesics with improved side effect profiles is currently a major focus for drug discovery. An important characteristic of neuropathic pain is hypersensitivity (allodynia) to normally innocuous cold stimuli (i.e. cold allodynia) (Hansson et al., 2001). In order to develop novel analgesic drugs several animal models of neuropathic pain have been established that mimic key pain symptoms as well as pathophysiological mechanisms and these models can be of utility to predict preclinical efficacy into humans (Wang and Wang, 2003). Two commonly used rodent models of neuropathic pain are the spared nerve injury model (SNI) and the spinal nerve lesion (SNL or Chung model), where animals are subjected to a partial nerve lesion of the sciatic nerve which in turn produces a high incidence of tactile and cold allodynia (Decosterd and Woolf, 2000, Kim and Chung, 1992, Erichsen and Blackburn-Munro, 2002).
Neuropathic pain is often resistant to treatment with conventional analgesics such as opioids (Dellemijn, 1999, Hao et al., 1999), therefore other classes of drugs such as anticonvulsants and tricyclic antidepressants are frequently used in ameliorating neuropathic pain (Rogawski and Loscher, 2004, Dickenson and Ghandehari, 2007). The anticonvulsants pregabalin and its close analogue gabapentin have recently appeared as alternative treatments for neuropathic pain (Bryans and Wustrow, 1999). Several in vivo behavioural studies have demonstrated that both pregabalin and gabapentin suppress static mechanical allodynia in rodents (Hunter et al., 1997, Field et al., 1997a, Field et al., 1997b, Field et al., 2000, Hwang and Yaksh, 1997, Cesena and Calcutt, 1999, Pan et al., 1999, Hao et al., 2000, Patel et al., 2001, Wallin et al., 2002, Erichsen and Blackburn-Munro, 2002, Fox et al., 2003, Gustafsson et al., 2003, Urban et al., 2005, Han et al., 2007, Takeuchi et al., 2007). However, dynamic mechanical allodynia as well as cold allodynia are more frequent and protruding symptoms in certain patients with neuropathic pain (Rosen et al., 1991, Hansson et al., 2001). In the present study, we aimed to replicate the clinical situation by further profiling the analgesic effects of pregabalin in the SNI and SNL models by using dynamic cold allodynia as readout. Cold allodynia was measured as the response to a cold spray stimulation using ethyl chloride (Hao et al., 1999, Erichsen and Blackburn-Munro, 2002). For comparison, the effect of pregabalin in a mechanistic model of neuropathic pain, i.e. the late phase of the formalin test, was also studied (Dickenson and Sullivan, 1987, Tjølsen et al., 1992). In addition, the side effect profile of pregabalin treatment on other centrally mediated behavioural functions, such as motor activity and anxiolytic behaviour was examined in naïve animals.
Section snippets
Animals
Experiments were performed in male Sprague-Dawley rats (n = 109 (analgesia testing) + 32 (locomotor activity), B&K Universal AB, Sollentuna, Sweden). The animals were housed in a temperature and humidity controlled environment on a 12 h light/dark cycle (lights on at 6:00 am). Food and water were freely available. The research protocol was approved by the regional ethical committee for experiments on laboratory animals. Experimental study groups were randomised and blinded.
Spared nerve injury (SNI) and spinal nerve ligation (SNL)
Under isoflurane
Effect of pregabalin on cold allodynia in SNI rats
Cold spray stimulation to the hind paw of nerve lesioned SNI rats resulted in cold allodynia (mean cumulative licking: 13.4 ± 1.4 s, n = 40), while intact naïve animals failed to elicit a significant pain response (licking behaviour). Single oral administration of pregabalin (single dosing, 30–300 µmol/kg) significantly reduced the pain response in a dose- and concentration dependent manner. The antiallodynic effect of pregabalin showed a slow onset (significant effects at 2.5 h after dosing) and
Discussion
We have used two different models of neuropathic pain, the SNI and the SNL model (Decosterd and Woolf, 2000, Kim and Chung, 1992), to demonstrate that oral administration of pregabalin, an anti-convulsant drug that has recently emerged as an alternative treatment for neuropathic pain, reverses cold allodynia in response to ethyl chloride spray stimulation. The pharmacodynamic profile of pregabalin was similar to what has been reported in other models of neuropathic pain with pregabalin and the
Acknowledgements
The authors would like to thank Yvonne Jaksch for bioanalysis of pregabalin, Vibeke Täpp, Sara Selenius and Angelica Hesselgren for excellent technical assistance during the in vivo experiments. The authors are also grateful to Carina Stenfors and Prof. Odd-Geir Berge for valuable comments on the manuscript.
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