Chronic inflammatory injury results in increased coupling of delta opioid receptors to voltage-gated Ca2+ channels

Molecular Pain

Wendy Walwyn¹  Christopher Evans¹  Brenna McGuire¹  Monique Smith¹  Amynah Pradhan¹ 

[1] Department of Neuropsychiatry and Biobehavioral Sciences, Stefan and Shirley Hatos Center for Neuropharmacology, Semel Institute, University of California, Los Angeles, CA, 90095, USA

关键词: Ca²⁺ channel;    Dorsal root ganglia;    Chronic pain;    Delta opioid receptor;    SNC80;    Primary afferent;   

Others  :  862602
DOI  :  10.1186/1744-8069-9-8

 received in 2012-09-28, accepted in 2013-02-25,  发布年份 2013

【 摘 要 】

Background

Opioid receptors regulate a diverse array of physiological functions. Mu opioid receptor agonists are well-known analgesics for treating acute pain. In contrast, animal models suggest that chronic pain is more effectively relieved by delta opioid receptor agonists. A number of studies have shown that chronic pain results in increased function of delta opioid receptors. This is proposed to result from enhanced trafficking of the delta opioid receptor to the cell membrane induced by persistent tissue injury. However, recent studies have questioned this mechanism, which has resulted in some uncertainty as to whether delta opioid receptors are indeed upregulated in chronic pain states. To clarify this question, we have examined the effect of chronic inflammatory pain over time using both an ex vivo measure of delta function: receptor-Ca²⁺ channel coupling, and an in vivo measure; the relief of chronic pain by a delta opioid receptor agonist. In addition, as beta-arrestin 2 can regulate delta opioid receptor trafficking and signaling, we have further examined whether deleting this scaffolding and signal transduction molecule alters delta opioid receptor function.

Results

We used the Complete Freund’s Adjuvant model of inflammatory pain, and examined the effectiveness of the delta agonist, SNC80, to both inhibit Ca²⁺ channels in primary afferent neurons and to attenuate mechanical allodynia. In naïve beta-arrestin 2 wildtype and knockout mice, SNC80 neither significantly inhibited voltage-dependent Ca²⁺ currents nor produced antinociception. However, following inflammatory pain, both measures showed a significant and long-lasting enhancement of delta opioid receptor function that persisted for up to 14 days post-injury regardless of genotype. Furthermore, although this pain model did not alter Ca²⁺ current density, the contribution of N-type Ca²⁺ channels to the total current appeared to be regulated by the presence of beta-arrestin 2.

Conclusions

Our results indicate that there is an upregulation of delta opioid receptor function following chronic pain. This gain of function is reflected in the increased efficacy of a delta agonist in both behavioral and electrophysiological measures. Overall, this work confirms that delta opioid receptors can be enhanced following tissue injury associated with chronic pain.

【 授权许可】

   
2013 Pradhan et al.; licensee BioMed Central Ltd.

【 图 表 】

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