Elsevier

Neuropharmacology

Volume 50, Issue 1, January 2006, Pages 111-122
Neuropharmacology

Development and expression of neuropathic pain in CB1 knockout mice

https://doi.org/10.1016/j.neuropharm.2005.07.022Get rights and content

Abstract

Neuropathic pain is a clinical manifestation characterized by the presence of spontaneous pain, allodynia and hyperalgesia. Here, we have evaluated the involvement of CB1 cannabinoid receptors in the development and expression of neuropathic pain. For this purpose, partial ligation of the sciatic nerve was performed in CB1 cannabinoid receptor knockout mice and their wild-type littermates. The development of mechanical and thermal allodynia, and thermal hyperalgesia was evaluated by using the von Frey filaments, cold-plate and plantar tests, respectively. Pre-surgical tactile and thermal withdrawal thresholds were similar in both genotypes. In wild-type mice, sciatic nerve injury led to a neuropathic pain syndrome characterized by a marked and long-lasting reduction of the paw withdrawal thresholds to mechanical and thermal stimuli. These manifestations developed similarly in mice lacking CB1 cannabinoid receptors. We have also investigated the consequences of gabapentin administration in these animals. Gabapentin (50 mg/kg/day, i.p.) induced a similar suppression of mechanical and thermal allodynia in both wild-type and CB1 knockout mice. Mild differences between genotypes were observed concerning the effect of gabapentin in the expression of thermal hyperalgesia. Taken together, our results indicate that CB1 cannabinoid receptors are not critically implicated in the development of neuropathic pain nor in the anti-allodynic and anti-hyperalgesic effects of gabapentin in this model.

Introduction

Neuropathic pain as a consequence of nerve injury is characterized by the presence of exaggerated response to painful stimuli (hyperalgesia), pain response to normally innocuous stimuli (allodynia) and spontaneous pain (Bridges et al., 2001a). These pathological pain sensations are associated with various complex physiological changes in the peripheral and central nervous system, such as spontaneous neuron discharging, alteration of ion channel expression, sprouting of primary afferent neurons, peripheral and central sensitisation, spinal reorganization and changes in inhibitory pain descending pathways (Basbaum, 1999, Baños et al., 2003, Wood et al., 2004). Due to the different adaptations occurred during neuropathic pain, a great diversity of pharmacological agents has been used to improve its symptomatology, including tricyclic antidepressants, NMDA receptor antagonists, local anaesthetics, GABA agonists, opioid agonists and anti-epileptic drugs, such as gabapentin. Actually, gabapentin is one of the most useful compounds to treat neuropathic pain in humans (Spina and Perugi, 2004, Maizels and Mc Carberg, 2005). However, majority of these treatments have a limited effectiveness or produce undesirable side effects (McQuay et al., 1996, Sindrup and Jensen, 1999, Baños et al., 2003, Foley, 2003, Lim et al., 2003). Recently, cannabinoids have emerged as new possible candidates for the treatment of neuropathic pain (Herzberg et al., 1997, Baños et al., 2003, Goya et al., 2003). Indeed, cannabinoid agonists reduce the allodynia and hyperalgesia that accompany neuropathies in experimental animals (Herzberg et al., 1997, Bridges et al., 2001b, Fox et al., 2001), although the specific mechanism of action remains unclear. Both CB1 and CB2 cannabinoid receptors may be involved in the anti-allodynic and anti-hyperalgesic effects of cannabinoids (Bridges et al., 2001b, Malan et al., 2002, Malan et al., 2003, Goya et al., 2003, Ibrahim et al., 2003, Costa et al., 2004, Scott et al., 2004). The high density of CB1 cannabinoid receptors in sensitive fibres of large diameter (Aβ and Aδ), which are associated to the aberrant pain transmission during neuropathies, could be a neuroanatomical site of action of cannabinoid agonists (Hohmann and Herkenham, 1999, Piomelli et al., 2000, Stander et al., 2005). CB2 receptors are located on non-neuronal cells in the vicinity of nociceptive neurons and seem to be involved in the modulation of pro-inflammatory agents such as prostaglandin E2 and nitric oxide (Costa et al., 2004).

Several anatomical studies in rats suggest the existence of an endogenous cannabinoid tone controlling the development of neuropathic pain symptoms. Thus, chronic constriction of the sciatic nerve induced a time dependent up-regulation of spinal CB1 cannabinoid receptors primarily within the ipsilateral superficial spinal cord dorsal horn (Lim et al., 2003). An up-regulation of CB1 cannabinoid receptors was also observed in the contralateral thalamic region after unilateral axotomy of the tibial branch of the sciatic nerve in rats (Siegling et al., 2001). In contrast, pharmacological studies have reported controversial results. Thus, the administration of the CB1 receptor antagonist, rimonabant, increased thermal hyperalgesia and mechanical allodynia in rats after a chronic constriction of the sciatic nerve (Herzberg et al., 1997), but not following L5/L6 spinal nerve ligation (Bridges et al., 2001b). The use of knockout mice lacking CB1 cannabinoid receptors represents a very useful tool to better understand the participation of the endocannabinoid system in the mechanisms underlying neuropathic pain. In our study, we have first evaluated the consequences of CB1 cannabinoid receptor deletion in the development and expression of neuropathic pain. Secondly, we have investigated whether the absence of CB1 cannabinoid receptors could modify the responses to one of the most current effective treatments for neuropathic pain, the anti-epileptic drug gabapentin, which mechanism of action for its analgesic effects remains unclear.

Section snippets

Animals

Male CB1 knockout mice and wild-type littermates weighing 26–30 g at the beginning of the experiments were used. The generation of mice lacking CB1 cannabinoid receptor was described previously (Ledent et al., 1999). In order to homogenize the genetic background of mice, the first generation heterozygous were bred for 15 generations on a CD1 background, with selection for the mutant CB1 gene at each generation. The CB1 receptor knockout mice derived from the backcrossing of chimeric CD1-CB1

Plantar test (thermal hyperalgesia)

Sciatic nerve ligature similarly decreased withdrawal latency of the ipsilateral hindpaw to a thermal stimulus in both CB1 knockout and wild-type mice (Fig. 1A, see Table 1 for two-way ANOVA). Baseline values were similar in both genotypes. Sham operation did not produce any modification of nociceptive response in wild-type and knockout mice. A marked and long-lasting decrease of paw withdrawal latency was observed in the ipsilateral paw of wild-type mice exposed to partial sciatic nerve injury

Discussion

In this study, we have investigated the role played by CB1 cannabinoid receptors in the development and expression of neuropathic pain in mice after partial sciatic nerve ligation. It is well established that injury to a peripheral nerve can lead to hyperalgesia to noxious thermal stimuli and allodynia to cold and mechanical stimuli in rodents, two features commonly observed in human neuropathies (Rowbotham, 1995). Partial ligation of the sciatic nerve in rodents presents the advantage of a

Acknowledgements

This work was supported by grants from the Spanish Ministerio de Ciencia y Tecnología (SAF 2004/0568 and GEN 2003-20651-C06-04), Redes del Instituto Carlos III (C 03/06 and G 03/005), and European Communities (QLRT 2001-01691 and NEWMOOD# LSHM-CT-2003-503474). AC is a fellowship from DURSI (Generalitat de Catalunya).

References (47)

  • U. Herzberg et al.

    The analgesic effects of R(+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain

    Neurosci. Lett.

    (1997)
  • A.G. Hohmann et al.

    Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study

    Neuroscience

    (1999)
  • A.H. Lichtman et al.

    Mice lacking fatty acid amide hydrolase exhibit a cannabinoid receptor-mediated phenotypic hypoalgesia

    Pain

    (2004)
  • G. Lim et al.

    Upregulation of spinal cannabinoid-1-receptors following nerve injury enhances the effects of win55,212-2 on neuropathic pain behaviours in rats

    Pain

    (2003)
  • W. Löscher et al.

    Gabapentin increases aminooxyacetic acid-induced GABA accumulation in several regions of rat brain

    Neurosci. Lett.

    (1991)
  • T.P. Malan et al.

    CB2 cannabinoid receptor agonists: pain relief without psychoactive effects?

    Curr. Opin. Pharmacol.

    (2003)
  • T.P. Malan et al.

    Inhibition of pain responses by activation of CB(2) cannabinoid receptors

    Chem. Phys. Lipids

    (2002)
  • A.B. Malmberg et al.

    Partial sciatic nerve injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates

    Pain

    (1998)
  • J. Mao et al.

    Two distinctive antinociceptive systems in rats with pathological pain

    Neurosci. Lett.

    (2000)
  • H.J. McQuay et al.

    A systematic review of antidepressants in neuropathic pain

    Pain

    (1996)
  • S. Patel 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)
  • R.G. Pertwee

    Cannabinoid receptors and pain

    Prog. Neurobiol.

    (2001)
  • D. Piomelli et al.

    The endocannabinoid system as a target for therapeutic drugs

    Trends Pharmacol. Sci.

    (2000)
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