Methylnaltrexone in the treatment of opioid-induced constipation

Constipation is a significant problem related to opioid medications used to manage pain. This review attempts to outline the latest findings related to the therapeutic usefulness of a μ opioid receptor antagonist, methylnaltrexone in the treatment of opioid-induced constipation. The review highlights methylnaltrexone bromide (Relistor™; Progenics/Wyeth) a quaternary derivative of naltrexone, which was recently approved in the United States, Europe and Canada. The Food and Drug Administration in the United States approved a subcutaneous injection for the treatment of opioid bowel dysfunction in patients with advanced illness who are receiving palliative care and when laxative therapy has been insufficient. Methylnaltrexone is a peripherally restricted, μ opioid receptor antagonist that accelerates oral–cecal transit in patients with opioid-induced constipation without reversing the analgesic effects of morphine or inducing symptoms of opioid withdrawal. An analysis of the mechanism of action and the potential benefits of using methylnaltrexone is based on data from published basic research and recent clinical studies

Sex Differences in Nociceptin/Orphanin FQ Peptide Receptor-Mediated Pain and Anxiety Symptoms in a Preclinical Model of Post-traumatic Stress Disorder

Nociceptin/Orphanin FQ (N/OFQ) is a neuropeptide that modulates pain transmission, learning/memory, stress, anxiety, and fear responses via activation of the N/OFQ peptide (NOP or ORL1) receptor. Post-traumatic stress disorder (PTSD) is an anxiety disorder that may arise after exposure to a traumatic or fearful event, and often is co-morbid with chronic pain. Using an established animal model of PTSD, single-prolonged stress (SPS), we were the first to report that NOP receptor antagonist treatment reversed traumatic stress-induced allodynia, thermal hyperalgesia, and anxiety-like behaviors in male Sprague-Dawley rats. NOP antagonist treatment also reversed SPS-induced serum and CSF N/OFQ increase and circulating corticosterone decrease. The objective of this study was to examine the role of the NOP receptor in male and female rats subjected to traumatic stress using Wistar wild type (WT) and NOP receptor knockout (KO) rats. The severity of co-morbid allodynia was assessed as change in paw withdrawal threshold (PWT) to von Frey and paw withdrawal latency (PWL) to radiant heat stimuli, respectively. PWT and PWL decreased in male and female WT rats within 7 days after SPS, and remained decreased through day 28. Baseline sensitivity did not differ between genotypes. However, while male NOP receptor KO rats were protected from SPS-induced allodynia and thermal hypersensitivity, female NOP receptor KO rats exhibited tactile allodynia and thermal hypersensitivity to the same extent as WT rats. Male NOP receptor KO rats had a lower anxiety index (AI) than WT, but SPS did not increase AI in WT males. In contrast, SPS significantly increased AI in WT and NOP receptor KO female rats. SPS increased circulating N/OFQ levels in male WT, but not in male NOP receptor KO, or WT or KO female rats. These results indicate that the absence of the NOP receptor protects males from traumatic-stress-induced allodynia and hyperalgesia, consistent with our previous findings utilizing a NOP receptor antagonist. However, female NOP receptor KO rats experience allodynia, hyperalgesia and anxiety-like symptoms to the same extent as WT females following SPS. This suggests that endogenous N/OFQ-NOP receptor signaling plays an important, but distinct, role in males and females following exposure to traumatic stress

Distribution of plasma membrane-associated syntaxins 1 through 4 indicates distinct trafficking functions in the synaptic layers of the mouse retina

BACKGROUND: Syntaxins 1 through 4 are SNAP receptor (SNARE) proteins that mediate vesicular trafficking to the plasma membrane. In retina, syntaxins 1 and 3 are expressed at conventional and ribbon synapses, respectively, suggesting that synaptic trafficking functions differ among syntaxin isoforms. To better understand syntaxins in synaptic signaling and trafficking, we further examined the cell- and synapse-specific expression of syntaxins 1 through 4 in the mouse retina by immunolabeling and confocal microscopy. RESULTS: Each isoform was expressed in the retina and showed a unique distribution in the synaptic layers of the retina, with little or no colocalization of isoforms. Syntaxin 1 was present in amacrine cell bodies and processes and conventional presynaptic terminals in the inner plexiform layer (IPL). Syntaxin 2 was present in amacrine cells and their processes in the IPL, but showed little colocalization with syntaxin 1 or other presynaptic markers. Syntaxin 3 was found in glutamatergic photoreceptor and bipolar cell ribbon synapses, but was absent from putative conventional glutamatergic amacrine cell synapses. Syntaxin 4 was localized to horizontal cell processes in the ribbon synaptic complexes of photoreceptor terminals and in puncta in the IPL that contacted dopaminergic and CD15-positive amacrine cells. Syntaxins 2 and 4 often were apposed to synaptic active zones labeled for bassoon. CONCLUSION: These results indicate that each syntaxin isoform has unique, non-redundant functions in synaptic signaling and trafficking. Syntaxins 1 and 3 mediate presynaptic transmitter release from conventional and ribbon synapses, respectively. Syntaxins 2 and 4 are not presynaptic and likely mediate post-synaptic trafficking

Selective loss of δ opioid analgesia and binding by antisense oligodeoxynucleotides to a δ opioid receptor

Antisense oligodeoxynucleotides (18–20 bases) to a cloned δ opioid receptor (DOR-1) lower δ binding in NG108-15 cells by 40%–50%. Changing 4 bases to generate a mismatch antisense oligodeoxynucleotide or mixing the corresponding sense and antisense oligodeoxynucleotides prior to treatment of the cells eliminates the inhibition of binding, confirming the specificity of the response. In vivo, an antisense oligodeoxynucleotide to DOR-1 given intrathecally lowers δ, but not μ or κ 1 spinal analgesia. The mismatch antisense oligodeoxynucleotide is inactive. δ analgesic sensitivity gradually returns by 5 days after the last antisense treatment, indicating the lack of irreversible damage or toxicity. These studies demonstrate that DOR-1 mediates δ analgesia at the level of the spinal cord and confirm at the molecular level traditional pharmacological studies implying distinct receptor mechanisms for δ, μ, and ϰ 1 analgesia. The use of antisense approaches may prove valuable in understanding the receptors mediating opioid pharmacology

FREQUENCY OF TRAUMAS IN LIBURNIAN POPULATION

<p><b>Copyright information:</b></p><p>Taken from "The presence of β-adrenoceptors sensitizes α-adrenoceptors to desensitization after chronic epinephrine treatment"</p><p>http://www.biomedcentral.com/1471-2210/7/16</p><p>BMC Pharmacology 2007;7():16-16.</p><p>Published online 20 Dec 2007</p><p>PMCID:PMC2234403.</p><p></p>o αand α) and αC4 (corresponding to α) gene products (Table 3). The reactions amplified fragments of the expected size from each set of primers. αC10/C4 primers amplified 233 bp products from SH-SY5Y mRNA that were sensitive to digestion by II (specific for the αproduct). Restriction digestion with XI of the 630 bp product of α 2C4 primer amplification gave three fragments of 271, 225 and 78 bp. All reactions were performed in the presence (+) or absence (-) of reverse transcriptase (RT) to rule out the possibility of DNA contamination. Lane M designates the 100 bp ladder; the 500 bp fragment is indicated by an arrow in each panel