Articles: neuropathic-pain.
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Cebranopadol is a novel and highly potent analgesic acting via nociceptin/orphanin FQ peptide (NOP) and opioid receptors. Since NOP and opioid receptors are expressed in the central nervous system as well as in the periphery, this study addressed the question of where cebranopadol exerts its effects in animal models of chronic neuropathic pain. Mechanical hypersensitivity in streptozotocin (STZ)-treated diabetic rats, cold allodynia in the chronic constriction injury (CCI) model in rats, and heat hyperalgesia and nociception in STZ-treated diabetic and control mice was determined after intraplantar (i.pl.), intracerebroventricular (i.c.v.), or intrathecal (i.th.) administration. ⋯ After central administration of cebranopadol, antihyperalgesic efficacy is reached at doses that are not yet antinociceptive. This study shows that cebranopadol is effective after peripheral as well as central administration in nociceptive and chronic neuropathic pain. Thus, it may be well-suited for the treatment of chronic pain conditions with a neuropathic component.
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The lower efficacy of opioids in neuropathic pain may be due to the increased activity of pronociceptive systems such as substance P. We present evidence to support this hypothesis in this work from the spinal cord in a neuropathic pain model in mice. Biochemical analysis confirmed the elevated mRNA and protein level of pronociceptive substance P, the major endogenous ligand of the neurokinin-1 (NK1) receptor, in the lumbar spinal cord of chronic constriction injury (CCI)-mice. ⋯ In naive mice, the single pharmacophore opioid parent compounds provided better analgesic results, as compared to the hybrids (max 70% MPE), raising the acute pain threshold close to 100% MPE. On the other hand, the opioid parents gave poor analgesic effects under neuropathic pain conditions, while the best hybrid delivered robust (close to 100% MPE) and long lasting alleviation of both tactile and thermal hypersensitivity. The results presented emphasize the potential of opioid/NK1 hybrids in view of analgesia under nerve injury conditions.
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The objectives of this study were to evaluate the methodological quality of rigorous neuropathic pain assessment tools in applicable clinical studies, and determine the performance of screening tools for identifying neuropathic pain in patients with cancer. ⋯ We identified concordance between the clinician diagnosis and screening tool outcomes for LANSS, DN4 and PDQ in patients with cancer pain. Shortcomings in relation to standardized clinician assessment are likely to account for variation in screening tool sensitivity, which should include the use of the neuropathic pain grading system. Further research is needed to standardize and improve clinical assessment in patients with cancer pain. Until the standardization of clinical diagnosis for neuropathic cancer pain has been validated, screening tools offer a practical approach to identify potential cases of neuropathic cancer pain.
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Upon systemic administration in rats, the prodrug L-4-chlorokynurenine (4-Cl-KYN; AV-101; VistaGen Therapeutics, Inc, South San Francisco, CA) is rapidly absorbed, actively transported across the blood-brain barrier, and converted in astrocytes to 7-chlorokynurenic acid (7-Cl-KYNA), a potent and specific antagonist of the glycine B coagonist site of the N-methyl-D-aspartate (NMDA) receptor. We examined the effects of 4-Cl-KYN in several rat models of hyperalgesia and allodynia and determined the concentrations of 4-Cl-KYN and newly produced 7-Cl-KYNA in serum, brain, and spinal cord. ⋯ Our conclusions show that after systemic delivery, the highest 2 doses (167 and 500 mg/kg) of 4-Cl-KYN yielded brain concentrations of 7-Cl-KYNA exceeding its half maximal inhibitory concentration (IC50) at the glycine B site and resulted in dose-dependent antihyperalgesia in the 4 models of facilitated processing associated with tissue inflammation and nerve injury. On the basis of the relative dose requirements for analgesic actions and side effect profiles from these experiments, 4-Cl-KYN is predicted to have antihyperalgesic efficacy and a therapeutic ratio equal to gabapentin and superior to MK-801.