CXCR4 signaling mediates morphine-induced tactile hyperalgesia

Abstract

Morphine and related compounds are the first line of therapy in the treatment of moderate to severe pain. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving into a painful response to previously non-noxious stimuli (opioid-induced hyperalgesia; OIH). The mechanism underlying OIH is not well understood although complex intracellular neural mechanisms, including opioid receptor desensitization and down-regulation, are believed to be major mechanisms underlying OIH. However, OIH may also be associated with changes in gene expression. A growing body of evidence suggests that cellular exposure to mu agonists upregulate chemokines/receptors and recent work from our lab implicates chemokine upregulation in a variety of neuropathic pain behaviors. Here we characterized the degree to which chemokines/receptors signaling is increased in primary afferent neurons of the dorsal root ganglion (DRG) following chronic morphine sulphate treatment and correlated these changes with tactile hyperalgesic behavior in rodents. We demonstrate that mRNA expression of the chemokine, stromal-derived factor-1 (SDF1/CXCL12) is upregulated following morphine treatment in sensory neurons of the rat. The release of SDF1 was found to be constitutive when compared with the activity dependent release of the C-C chemokine, monocyte chemoattractant protein-1 (MCP1/ CCL2) in a line of F-11 neuroblastoma-sensory neuron hybrid cells. We further determined that there is pronounced CXCR4 expression in satellite glial cells and following morphine treatment, increased functional CXCR4 expression in sensory neurons of the DRG. Moreover, intraperitoneal administration of the specific CXCR4 antagonist, AMD3100, completely reversed OIH in the rat. Taken together; the data suggest that opioid-induced SDF1/CXCR4 signaling is central to the development of long lasting OIH and that receptor antagonists represent a promising novel

CXCL12/CXCR4 axis: an emerging neuromodulator in pathological pain

“…Recently, evidence from an in vivo study directly proves that CXCL12/CXCR4 axis was essential to the pathology of OIH (Wilson et al, 2011). In this study, it was found that repeated intraperitoneal injection of morphine induced tactile hyperalgesia, which was attenuated by intraperitoneal administration of AMD3100 in rats.…”

“…Even though some reasons for the poor response have been proposed, like pharmacokinetic properties, species selectivity, and drug metabolism (Gao and Ji, 2010), an effective solution to this problem has not been reported. In our previous study, it was found that the antiallodynia effects of AMD3100 by injecting centrally lasted for 3-4 days (Luo et al, 2014), but such effects by injecting peripherally only lasted for hours (Bhangoo et al, 2007b(Bhangoo et al, , 2009Dubovy et al, 2010;Wilson et al, 2011). Therefore, we hypothesize that the efficacy of CXCL12/CXCR4 axis-related therapy may depend on how it is delivered, and more evidence is needed to prove this.…”

“…The interaction between chemokine and opioid system has been considered an emerging target to improve the efficacy of opioid therapy . As CXCL12/CXCR4 axis is central for the pathology of opioid tolerance (Rivat et al, 2014) and OIH (Wilson et al, 2011), the blockade of CXCL12/CXCR4 axis could be an adjunctive strategy for opioid therapy. Therefore, preclinical and/ or clinical studies on this topic are necessary to evaluate such possibility.…”

Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells

“…Previous studies showed that CXCL12 and CXCR4 actively participate in nociception via direct stimulation of nociceptive neurons (23), via induction of mechanical hypersensitivity in rats (24), or via desensitization of opioid receptors, but all these effects are in the central nervous system (25). In the present study, we show this chemokine-receptor axis has a role in the activation of peripheral glia, i.e., SC, in the tumor microenvironment, which seems to entail an analgesic effect in the early disease course.…”

Upregulation of Chemokine CXCL12 in the Dorsal Root Ganglia and Spinal Cord Contributes to the Development and Maintenance of Neuropathic Pain Following Spared Nerve Injury in Rats

“…The binding of CXCL12 to CXCR4 activates multiple signaling pathways, including the extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase-Akt, cAMP/ cAMP-dependent protein kinase, and phospholipase C pathways, and results in increased intracellular calcium levels and the release of cytokines by glial cells [8][9][10]. Increasing evidence suggests that CXCL12/CXCR4 play important roles in nociceptive signal processing [11][12][13][14]. They are widely distributed and constitutively expressed in small amounts in small-and medium-sized dorsal root ganglia (DRG) neurons and glia (satellite cells) and in the spinal cord [15,16].…”