Neuropharmacology and Analgesia
Oral pregabalin reverses cold allodynia in two distinct models of peripheral neuropathic pain

https://doi.org/10.1016/j.ejphar.2009.01.014Get rights and content

Abstract

A major symptom of persistent neuropathic pain, which may develop after peripheral nerve injury, is hypersensitivity (allodynia) to normally innocuous cold stimuli. Although the anticonvulsant pregabalin has been demonstrated to relieve neuropathic pain, both in preclinical models and clinically, the analgesic effect of the drug in animals has not been profiled for cold hypersensitivity. Therefore, we examined the effect of pregabalin (single oral dosing: 30, 100, 300 μmol/kg) on cold allodynia in two models of chronic neuropathic pain, the spared nerve injury (SNI) and the spinal nerve ligation (SNL) models. A significant antiallodynic effect was observed with pregabalin at all doses tested with a maximal effect of 71% (SNI) and 60% (SNL), respectively compared to vehicle. For comparison, only the highest dose tested of pregabalin (300 μmol/kg), significantly decreased pain responses in phase 2 of the rat formalin test (∼ 67% pain inhibition). However, pregabalin at this high dose also affected other centrally mediated behavioural functions, such as motor activity and anxiolytic behaviour in naïve animals, which could potentially interfere with the pain readout. The present study demonstrates that oral administration of pregabalin significantly reduces both cold allodynia induced in the SNI and the SNL models of neuropathic pain as well as formalin-induced nociception, albeit with different sensitivity and potency.

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.

References (48)

  • HwangJ.H. et al.

    Effect of subarachnoid gabapentin on tactile-evoked allodynia in a surgically induced neuropathic pain model in the rat

    Reg. Anesth.

    (1997)
  • LiuC.N. et al.

    Tactile allodynia in the absence of C-fiber activation: altered firing properties of DRG neurons following spinal nerve injury

    Pain

    (2000)
  • LynchJ.J. et al.

    (L)-Phenylglycine, but not necessarily other alpha2delta subunit voltage-gated calcium channel ligands, attenuates neuropathic pain in rats

    Pain

    (2006)
  • PatelS. et al.

    The effects of GABA(B) agonists and gabapentin on mechanical hyperalgesia in models of neuropathic and inflammatory pain in the rat

    Pain

    (2001)
  • RichterR.W. et al.

    Relief of painful diabetic peripheral neuropathy with pregabalin: a randomised, placebo-controlled trial

    J. Pain

    (2005)
  • RosenstockJ. et al.

    Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial

    Pain

    (2004)
  • SabatowskiR. et al.

    Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial

    Pain

    (2004)
  • TakeuchiY. et al.

    Pregabalin, S-(+)-3-isobutylgaba, activates the descending noradrenergic system to alleviate neuropathic pain in the mouse partial sciatic nerve ligation model

    Neuropharmacology

    (2007)
  • TjølsenA. et al.

    The formalin test: an evaluation of the method

    Pain

    (1992)
  • VissersK.C.P. et al.

    Pharmacological correlation between the formalin test and the neuropathic pain behaviour in different species with chronic constriction injury

    Pharmacol. Biochem. Behav.

    (2006)
  • WallinJ. et al.

    Gabapentin and pregabalin suppress tactile allodynia and potentiate spinal cord stimulation in a model of neuropathy

    Eur. J. Pain

    (2002)
  • WangL.X. et al.

    Animal and cellular models of chronic pain

    Adv. Drug Deliv. Rev.

    (2003)
  • WeltyD.F. et al.

    Gabapentin anticonvulsant action in rats: disequilibrium with peak drug concentrations in plasma and brain microdialysate

    Epilepsy Res.

    (1993)
  • AttalN.

    Chronic neuropathic pain: mechanisms and treatment

    Clin. J. Pain

    (2000)
  • Cited by (27)

    • Clinically relevant concentration of pregabalin has no acute inhibitory effect on excitation of dorsal horn neurons under normal or neuropathic pain conditions: An intracellular calcium-imaging study in spinal cord slices from adult rats

      2016, Brain Research
      Citation Excerpt :

      These results confirmed the potential ability of our approach to detect an inhibitory effect of pregabalin (if present) on the excitability of dorsal horn neurons. According to studies in humans (Buvanendran et al., 2010) and animals (Gustafsson and Sandin, 2009), if pregabalin is administered at effective analgesic doses, its peak concentration in the CNS is <10 μM. Therefore, first we examined whether pregabalin (10 μM) attenuates dorsal root-evoked excitation of dorsal horn neurons under normal conditions and whether its effect becomes more pronounced after the development of painful diabetic neuropathy.

    • Early treatment with UR13870, a novel inhibitor of p38α mitogenous activated protein kinase, prevents hyperreflexia and anxiety behaviors, in the spared nerve injury model of neuropathic pain

      2015, Neuroscience Letters
      Citation Excerpt :

      The UR13870 dose was chosen based on its functional and anti-inflammatory effect observed in the collagen-induced arthritis model [13]. Pregabalin was included in the study as a positive control for its pharmacological properties in peripheral nerve injury models.[14] Motor and hyperreflexia tests were performed before the injury and at days 3, 5, 7, 10 and 14 after SNI.

    View all citing articles on Scopus
    View full text