Journal of pharmacological sciences
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Individual differences in the sensitivity to fentanyl, a widely used opioid analgesic, can hamper effective pain treatment. The adrenergic system is reportedly involved in the mechanisms of pain and analgesia. Here, we focused on one of the adrenergic receptor genes, ADRB1, and analyzed the influence of single-nucleotide polymorphisms (SNPs) in the ADRB1 gene on individual differences in pain and analgesic sensitivity. ⋯ The analgesic effect was significantly less in females who carried the G-allele of the G1165C SNP than the females who did not carry the G-allele. The haplotype analysis revealed a significant decrease in 24-h postoperative fentanyl use in female 145A/1165C haplotype carriers. These results suggest that SNPs in the ADRB1 gene are associated with individual differences in pain and analgesic sensitivity, and analyzing these SNPs may promote personalized pain treatment in the future.
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Transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+)-permeable non-selective cation channel that transmits pain signals. TRPV1 is activated by multiple stimuli such as capsaicin, acid, and heat. During inflammation, TRPV1 is reported to be sensitized by protein kinase C (PKC) in dorsal root ganglia (DRG) neurons, which leads to reduction in the threshold of the temperature for TRPV1 activation to body temperature. ⋯ The potentiation of heat-induced inward currents by PKC was seen in rat DRG neurons, and K-685 attenuated these currents. Furthermore, K-685 reversed the thermal hyperalgesia and mechanical allodynia in a rat complete Freund's adjuvant-induced inflammatory pain model. These results therefore suggest that K-685 has a strong potential as a new analgesic drug for the treatment of inflammatory pain.
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Chronic pain refractory to non-steroidal anti-inflammatory drugs (NSAIDs) is a major problem and drugs for such pain are needed. Many studies suggest that transient receptor potential vanilloid type 1 (TRPV1) is associated with NSAID-refractory chronic pain. Therefore, we investigated the involvement of TRPV1 in NSAID-refractory chronic pain using experimental models for NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. ⋯ JTS-653 did not affect the nociception of noxious thermal and mechanical stimuli and motor coordination in normal rats. These findings demonstrate the TRPV1 involvement in NSAID-refractory chronic pain reflecting severe arthritic and postherpetic pain. TRPV1 antagonists would be useful for the treatment of NSAID-refractory chronic pain.
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Neuropathic pain induces allodynia and hyperalgesia. In the spared nerve injury (SNI) model, marked mechanical hyperalgesia is manifested as prolongation of the duration of paw withdrawal after pin stimulation. We have previously reported that spinal ventral root discharges (after-discharges) after cessation of noxious mechanical stimulation applied to the corresponding hindpaw were prolonged in anesthetized spinalized rats. ⋯ Moreover, resiniferatoxin eliminated after-discharges completely. These results show that TRPV1-positive fibers do not participate in the mechanical allodynia caused by sensitization of Aβ-fibers, but contribute to the enhancement of after-discharges and mechanical hyperalgesia following SNI. It is suggested that the mechanisms responsible for generating mechanical allodynia differ from those for prolongation of mechanical hyperalgesia.
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We evaluated the effect of buprenorphine, a mixed agonist for μ-opioid receptors and nociceptin/orphanin FQ peptide (NOP) receptors, in neuropathic rats, using the paw pressure test. Buprenorphine, administered i.p. at 50, but not 20, μg/kg, exhibited naloxone-reversible analgesic activity in naïve rats. ⋯ Intrathecal injection of [N-Phe(1)]nociceptin(1-13)NH2, a NOP-receptor antagonist, reversed the effect of buprenorphine in neuropathic rats, but not in naïve rats. Together, buprenorphine suppresses neuropathic hyperalgesia by activating NOP and opioid receptors, suggesting its therapeutic usefulness in treatment of neuropathic pain.