Changes in morphine reward in a model of neuropathic pain.

In addition to sensory disturbances, neuropathic pain is associated with an ongoing and persistent negative affective state. This condition may be reflected as altered sensitivity to rewarding stimuli. We examined this hypothesis by testing whether the rewarding properties of morphine are altered in a rat model of neuropathic pain. Neuropathic pain was induced by chronic constriction of the common sciatic nerve. Drug reward was assessed using an unbiased, three-compartment conditioned place preference (CPP) paradigm. The rats underwent two habituation sessions beginning 6 days after surgery. Over the next 8 days, they were injected with drug or vehicle and were confined to one CPP compartment for 30 min. On the following test day, the rats had access to all three compartments for 30 min. Consistent with the literature, systemic administration of morphine dose-dependently increased the CPP in pain-naive animals. In rats with neuropathic pain, however, the dose-dependent effects of morphine were in a bell-shaped curve, with a low dose of morphine (2 mg/kg) producing a greater CPP than a higher dose of morphine (8 mg/kg). In a separate group of animals, acute administration of morphine reversed mechanical allodynia in animals with neuropathic pain at the same doses that produced a CPP. The increased potency of systemic morphine to produce a CPP in animals with neuropathic pain suggests that the motivation for opioid-induced reward is different in the two states

Changes in morphine reward in a model of neuropathic pain.

In addition to sensory disturbances, neuropathic pain is associated with an ongoing and persistent negative affective state. This condition may be reflected as altered sensitivity to rewarding stimuli. We examined this hypothesis by testing whether the rewarding properties of morphine are altered in a rat model of neuropathic pain. Neuropathic pain was induced by chronic constriction of the common sciatic nerve. Drug reward was assessed using an unbiased, three-compartment conditioned place preference (CPP) paradigm. The rats underwent two habituation sessions beginning 6 days after surgery. Over the next 8 days, they were injected with drug or vehicle and were confined to one CPP compartment for 30 min. On the following test day, the rats had access to all three compartments for 30 min. Consistent with the literature, systemic administration of morphine dose-dependently increased the CPP in pain-naive animals. In rats with neuropathic pain, however, the dose-dependent effects of morphine were in a bell-shaped curve, with a low dose of morphine (2 mg/kg) producing a greater CPP than a higher dose of morphine (8 mg/kg). In a separate group of animals, acute administration of morphine reversed mechanical allodynia in animals with neuropathic pain at the same doses that produced a CPP. The increased potency of systemic morphine to produce a CPP in animals with neuropathic pain suggests that the motivation for opioid-induced reward is different in the two states

Impact of a CXCL12/CXCR4 Antagonist in Bleomycin (BLM) Induced Pulmonary Fibrosis and Carbon Tetrachloride (CCl4) Induced Hepatic Fibrosis in Mice.

Modulation of chemokine CXCL12 and its receptor CXCR4 has been implicated in attenuation of bleomycin (BLM)-induced pulmonary fibrosis and carbon tetrachloride (CCl4)-induced hepatic injury. In pulmonary fibrosis, published reports suggest that collagen production in the injured lung is derived from fibrocytes recruited from the circulation in response to release of pulmonary CXCL12. Conversely, in hepatic fibrosis, resident hepatic stellate cells (HSC), the key cell type in progression of fibrosis, upregulate CXCR4 expression in response to activation. Further, CXCL12 induces HSC proliferation and subsequent production of collagen I. In the current study, we evaluated AMD070, an orally bioavailable inhibitor of CXCL12/CXCR4 in alleviating BLM-induced pulmonary and CCl4-induced hepatic fibrosis in mice. Similar to other CXCR4 antagonists, treatment with AMD070 significantly increased leukocyte mobilization. However, in these two models of fibrosis, AMD070 had a negligible impact on extracellular matrix deposition. Interestingly, our results indicated that CXCL12/CXCR4 signaling has a role in improving mortality associated with BLM induced pulmonary injury, likely through dampening an early inflammatory response and/or vascular leakage. Together, these findings indicate that the CXCL12-CXCR4 signaling axis is not an effective target for reducing fibrosis

AMD070 had no effect on CCl₄ induced liver fibrosis in C57BL/6 mice.

<p>Liver fibrosis was measured using Picosirius red and scored percent areas are shown in panel (A). Panels from each of the treatment groups contain representative Picrosirius Red stained left top lobe of livers from the oil plus PBS (B), CCl₄ plus PBS (C) and CCl₄ plus AMD070 (D) groups respectively. Bars represent 1 mm for the top image and 50 μm for the lower images in each panel.</p

PO administration of AMD070 increased leukocyte mobilization.

<p>Cell counts in the blood of CD-1 mice at various times after the PO administration of AMD070 at either 200 (A) or 400 (B) μg/mouse. Data shown are WBCs (●; x 10³/μL), RBCs (■; x 10⁶/μL) and platelets (▲ x 10⁶/μL) and are the means (± SEM) of 3 animals.</p

IP administration of AMD070 increased leukocyte mobilization.

<p>Cell counts in the blood of C57BL/6 mice at various times following the IP administration of AMD070 at 400 μg/mouse. A comparison of the numbers of WBCs(●; x 10³/μL), RBCs (■; x 10⁶/μL) and platelets (▲; x 10⁶/μL) are shown in panel (A) and are the means (± SEM) of 4 animals. Differential cell counts at various times are shown in panel (B) for lymphocytes (■), neutrophils (●), monocytes (▲) and eosinophils (▼) and are the means (± SEM) of 4 animals.</p

Leukocyte mobilization induced by AMD070 was the result of increase in lymphocytes.

<p>Differential cell counts in the blood of CD-1 mice at various times following PO administration of AMD070 at either 200 (A) or 400 (B) μg/mouse. Data are shown for lymphocytes (■), neutrophils (●), monocytes (▲) and eosinophils (▼) and are the means (± SEM) of 3 animals.</p

AMD070 alleviated BLM induced mortality.

<p>Kaplan Meier plot of animals in the PBS plus acetate buffer, BLM plus acetate buffer and BLM plus AMD070 groups.</p

Phoenix WinNonlin Noncompartmental analysis of AMD070 concentration in the plasma, lung and liver of C57BL/6 mice following IP or SC administration of AMD070 at 400 μg/mouse.

<p>Values for Cmax are provided as μg/mL for plasma and as μg/g for liver and lung. Values for AUC are provided as μg/mL for plasma and as μg/g for lung and liver.</p

AMD070 did not alleviate BLM induced lung inflammation at end point as demonstrated by H & E stained lungs.

<p>Graph in (A) represents the means (± SEM) of percent surface area with high inflammatory cell infiltrate, as measured by H&E staining intensity. Representative H & E stained lungs of PBS plus acetate buffer (B), BLM plus acetate buffer (C) and BLM plus AMD070 (D) treated mice. Black arrows indicate areas with increased inflammatory cell infiltrate. AB indicates acetate buffer and this notation is used for the following Figs.</p