Articles: hyperalgesia.
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Narcotic bowel syndrome (NBS) is a subset of opioid bowel dysfunctions that results from prolonged treatment with narcotics and is characterized by chronic abdominal pain. NBS is under-recognized and its molecular mechanisms are unknown. We aimed to (1) develop a rat model of NBS and (2) to investigate its peripheral and central neurobiological mechanisms. ⋯ We developed a rat model of narcotic bowel-like syndrome and showed that spinal microglia activation mediates the development of morphine-induced visceral hyperalgesia; peripheral neuroimmune activation and spinal dynorphin release represent an important mechanism in the delayed and long-lasting morphine-induced colonic hypersensitivity response to CRD.
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Exp Clin Psychopharmacol · Aug 2010
Repeated administration of pioglitazone attenuates development of hyperalgesia in a rat model of neuropathic pain.
Recent studies indicate the central neuroimmune and neuroinflammation activation play a critical role in the pathological states of pain. Pioglitazone, a potent synthetic agonists of PPARgamma, has shown to control neuroinflammation in many nervous system-related disorders. The present study was designed to explore the effects of pioglitazone in treating neuropathic pain and its possible neuroimmune mechanisms in the neuropathic pain using lumbar 5 (L5) spinal nerve transection rat model. ⋯ We found that pioglitazone (5 and 10 mg/kg) can markedly attenuate mechanical hyperalgesia produced by nerve transection, most significantly on the 14th day. The elevated TNF-alpha, IL-1beta, and NF-kappaB in brain were accordingly reduced. Our data could conclude that pioglitazone has ameliorative potential in attenuating the painful state associated with L5 nerve transection, which may further be attributed to inhibiting cerebral proinflammatory cytokines production and NF-kappaB activation in central nervous system.
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J. Pharmacol. Exp. Ther. · Aug 2010
Pharmacokinetic-pharmacodynamic analysis of the static allodynia response to pregabalin and sildenafil in a rat model of neuropathic pain.
The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of the static allodynia response to pregabalin with and without sildenafil in a chronic constriction injury model of neuropathic pain. Six treatment groups were evaluated every 30 min for 6 h. Rats were treated with either 1) a saline infusion; 2) a 2-h pregabalin infusion at 4 mgxkg(-1)xh(-1); 3) a 2-h pregabalin infusion at 10 mgxkg(-1)xh(-1); 4) a 2.2-mg loading dose + 12 mgxkg(-1)xmin(-1) infusion of sildenafil; 5) a 2-h pregabalin infusion at 1.6 mgxkg(-1)xh(-1) with sildenafil; and 6) a 2-h infusion of pregabalin at 4 mgxkg(-1)xh with sildenafil. ⋯ Likewise, the continuous PK-PD models demonstrated a reduction in the EC(50) of pregabalin necessary for PD response in the presence of sildenafil. The difference-transformed PD model resulted in a 54.4% (42.3-66.9%) decrease in EC(50), whereas the percentage-transformed PD model demonstrated a 53.5% (42.7-64.3%) shift. It is concluded from these studies that there is a synergistic PD interaction between pregabalin and sildenafil.
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Journal of neurochemistry · Aug 2010
Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice.
The chemokine fractalkine (FKN) is a critical mediator of spinal neuronal-microglial communication in chronic pain. Mature FKN is enzymatically cleaved from neuronal membranes and activation of its receptor, CX3CR1, which is expressed by microglia, induces phosphorylation of p38 MAPK. We used CX3CR1 knockout (KO) mice to examine pain behaviour in the absence of FKN signalling. ⋯ In WT mice, inflammation and nerve injury increased spinal cord CX3CR1 and FKN expression. FKN protein was also increased in KO mice following inflammation but not after neuropathy, suggesting the FKN/CX3CR1 system is differently affected in the two pain models. Loss of FKN/CX3CR1 neuroimmune communication attenuates hyperalgesia and allodynia in a modality-dependent fashion highlighting the complex nature of microglial response in pathological pain models.
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Lysophosphatidic acid (LPA) is released from injured tissue and cancer cells and is involved in the induction of neuropathic pain. The present study explores whether LPA plays a role in the development of osteocarcinoma-induced pain. ⋯ These data indicate that LPA is involved in the induction of bone cancer pain through mechanisms of peripheral C-fibers sensitization. LPA and its downstream molecules possibly are promising therapeutic targets for treatment of cancer pain.