Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Analgesic effects of delta opioid receptor (DOR) -selective agonists are enhanced during persistent inflammation and arthritis. Although the underlying mechanisms are still unknown, membrane density of DOR was shown to be increased 72 h after induction of inflammation, an effect abolished in mu opioid receptor (MOR) -knockout (KO) mice [Morinville A, Cahill CM, Kieffer B, Collier B, Beaudet A (2004b) Mu-opioid receptor knockout prevents changes in delta-opioid receptor trafficking induced by chronic inflammatory pain. Pain 109:266-273]. In this study, we demonstrated a crucial role of MOR in DOR-mediated antihyperalgesia. Intrathecal administration of the DOR selective agonist deltorphin II failed to induce antihyperalgesic effects in MOR-KO mice, whereas it dose-dependently reversed thermal hyperalgesia in wild-type mice. The antihyperalgesic effects of deltorphin II were blocked by naltrindole but not d-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) suggesting that this agonist was mainly acting through DOR. SNC80-induced antihyperalgesic effects in MOR-KO mice were also attenuated as compared with littermate controls. In contrast, kappa opioid receptor knockout did not affect deltorphin II-induced antihyperalgesia. As evaluated using mice lacking endogenous opioid peptides, the regulation of DOR's effects was also independent of beta-endorphin, enkephalins, or dynorphin opioids known to be released during persistent inflammation. We therefore conclude that DOR-mediated antihyperalgesia is dependent on MOR expression but that activation of MOR by endogenous opioids is probably not required.
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PMID:Essential role of mu opioid receptor in the regulation of delta opioid receptor-mediated antihyperalgesia. 1799 30

Previous reports from our laboratory described the sedative activity of hesperidin (hesperetin-7-rhamnoglucoside). This property is greatly increased when the glycoside is injected jointly with diazepam and this interaction has been shown to be synergistic. In the present work the generality of the synergistic phenomenon is proved, since potentiation also occurs with several other benzodiazepines, namely alprazolam, bromazepam, midazolam and flunitrazepam. In order to advance in the study of the mechanism of action of hesperidin, the possible participation of several brain receptors, which are implicated in the control of numerous behavioral and physiological functions, was explored by investigating the effects of a variety of their antagonists on hesperidin actions. The results showed that the 5-HT2 receptor and the alpha1-adrenoceptor seem unlikely to be involved in the behavioral effects of hesperidin. Naltrexone, a nonselective antagonist of opioid receptors, totally blocked hesperidin effects on locomotion, and partially antagonized hesperidin-induced decreased exploration in the hole board test. Nor-binaltorphimine, a selective kappa opioid receptor antagonist, was able to partially block hesperidin effects on locomotor activity. Furthermore, hesperidin-induced antinociception was partially blocked by naltrexone, and potentiated by co-administration with alprazolam. Hence, the participation of the opioid system in the sedative, antinociceptive and potentianting effects of hesperidin with benzodiazepines in mice is highly probable. Our results suggest a possible beneficial use of the association of hesperidin with benzodiazepines, not only to improve human sedative therapy, but also in the management of pain.
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PMID:Opioid receptors are involved in the sedative and antinociceptive effects of hesperidin as well as in its potentiation with benzodiazepines. 1804 26

Multiple sclerosis patients typically experience increased pain that is relatively insensitive to opiate treatment. The mechanistic basis for this increased nociception is currently poorly understood. In the present study, we utilized the Theiler's murine encephalomyelitis virus (TMEV) model of MS to examine possible changes in spinal cord opioid receptor mRNA over the course of disease progression. TMEV infection led to significantly decreased mu, delta and kappa opioid receptor mRNA expression as analyzed by quantitative real-time PCR in both male and female mice at days 90, 150 and 180 post-infection (PI). Since opioid receptor mRNA expression decreased in TMEV mice, we examined whether opiate analgesia is also altered. TMEV infected female mice had significantly decreased opiate analgesia in thermal nociceptive tests beginning at day 90 PI, while TMEV-infected male mice did not display significantly decreased opiate analgesia until day 120 PI. The novel finding that opioid receptor expression is significantly decreased in the spinal cord of TMEV mice could explain the increased nociception and loss of opiate analgesia observed in both TMEV mice and multiple sclerosis patients.
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PMID:Decreased spinal cord opioid receptor mRNA expression and antinociception in a Theiler's murine encephalomyelitis virus model of multiple sclerosis. 1809 40

In an effort to reduce or eliminate the centrally associated side effects produced by opioid analgesics there has been an interest in the preparation of peripherally acting opioid receptor agonists. These compounds would have very limited or no access to the central nervous system. As a first step towards developing peripheral kappa opioid receptor (KOP) agonists, we have developed a quantitatively predictive chemical function-based pharmacophore model of selective kappa opioid receptor agonists by using the HypoGen algorithm implemented in the Catalyst software. The input for HypoGen was a training set of 26 KOP agonists exhibiting K(i) values ranging between 0.015nM and 2300nM. The best output hypothesis consists of four features: one hydrophobic (HYD), one ring aromatic (RA), one hydrogen bond acceptor (HBA), and one positive ionizable (PI) function. The predictive power of the model could be demonstrated by internal and external validation of the generated hypothesis. The resulting Catalyst pharmacophore can be used concurrently for rapid virtual screening of chemical databases to identify novel, selective KOP agonists that may be easily restricted to target tissues by synthetic modification. It is anticipated that such an approach will lead to the generation of novel selective KOP agonists that are clinically useful for the treatment of pain through peripheral mechanisms.
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PMID:Chemical function-based pharmacophore development for novel, selective kappa opioid receptor agonists. 1845 26

Recently, it has been known that the antinociception of sildenafil, a phosphodiesterase 5 inhibitor, is mediated through the opioid receptors. There are common three types of opioid receptors mu, delta, and kappa. We characterized the role of subtypes of opioid receptor for the antinociception of sildenafil at the spinal level. Intrathecal catheters were placed for drug delivery and formalin solution (5%, 50 microl) was injected for induction of nociception within male SD rats. The effect of mu opioid receptor antagonist (CTOP), delta opioid receptor antagonist (naltrindole), and kappa opioid receptor antagonist (GNTI) on the activity of sildenafil was examined. Intrathecal sildenafil decreased the flinching responses during phases 1 and 2 in the formalin test. Intrathecal CTOP and naltrindole reversed the antinociception of sildenafil during both phases in the formalin test. Intrathecal GNTI reversed the effect of sildenafil during phase 2, but not phase 1. These results suggest that sildenafil is effective to acute pain and the facilitated pain state at the spinal level. Both mu and delta opioid receptors are involved. However, it seems that kappa opioid receptors play in the effect of sildenafil.
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PMID:Roles of opioid receptor subtypes on the antinociceptive effect of intrathecal sildenafil in the formalin test of rats. 1858 61

Analgesic tolerance to morphine can develop from long-term use of this drug for the treatment of pain. Many reports have shown that stimulation of the kappa opioid receptor (KOR) suppresses development of analgesic tolerance to morphine. Here, we studied the KOR-mediated inhibition of morphine tolerance during repeated morphine treatment, with a focus on desensitization of the receptor. The development of analgesic tolerance to morphine during repeated morphine administration (10 mg kg(-1) s.c.) was completely suppressed by U-50488H (2 mg kg(-1) i.p.), a KOR agonist. The decrease in [35S] GTPgammaS binding activity stimulated by the mu opioid receptor (MOR) agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) was also significantly inhibited by U-50488H. These results indicate that stimulation of KOR caused by repeated morphine treatment either inhibits MOR desensitization or accelerates recycling of MOR on the cell surface, thereby suppressing morphine tolerance. Furthermore, we found that activity of protein kinase C (PKC) was significantly decreased in mice treated with both U-50488H and morphine. These results suggest that the mechanisms underlying KOR-mediated inhibition of analgesic tolerance to morphine may be partly due to suppression of PKC activation and prevention of receptor desensitization.
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PMID:Involvement of kappa opioid receptors in the inhibition of receptor desensitization and PKC activation induced by repeated morphine treatment. 1871 22

Nociceptin, also known as orphanin FQ, is a opioid-like neuropeptide that mediates its effects at the nociceptin receptor, a member of the G protein-coupled receptor superfamily. In mammals, nociceptin produces analgesia after spinal administration, however the role of nociceptin and nociceptin receptors in the modulation of noxious stimuli in non-mammalian species has not been examined. In an amphibian pain model using the acetic acid test with Rana pipiens, nociceptin and nociceptin1-13 amide produced dose-dependent antinociception (1-100 nmol), blocked by the nociceptin antagonist, [Nphe1]-nociceptin1-13 amide (30 nmol), but not the opioid antagonist, naltrexone (100 nmol/g, s.c.). Conversely, the antinociceptive effects of micro, delta, and kappa opioid receptor agonists were not blocked by the nociceptin antagonist. Nociceptin and nociceptin1-13 amide were the least potent of the opioid agonists tested. These studies demonstrate that spinal nociceptin receptors and not opioid receptors mediate the antinociceptive effect of nociceptin. Considered with previous findings, these behavioral data supports a role for nociceptin inhibition of spinal nociception in amphibians and perhaps all vertebrates.
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PMID:Nociceptin produces antinociception after spinal administration in amphibians. 1880 20

This study examined the association between pressure pain sensitivity and various single nucleotide polymorphisms (SNPs) of human micro-, kappa-, and delta-opioid receptor (i.e. OPRM1, OPRK1, and OPRD1) genes in 72 healthy adult Taiwanese women of Han Chinese race. Pressure pain threshold and tolerance were measured by an algometer and polymorphisms of the opioid receptor genes determined from blood samples. Our data revealed that pressure pain threshold, but not tolerance, in subjects with the minor allele (termed 'GA') genotype of the IVS2+31G>A polymorphism of the OPRM1 gene was significantly higher than those with major allele (termed 'GG') genotype. Neither pressure pain threshold nor tolerance between major and minor alleles of other SNPs of the OPRM1, OPRK1, and OPRD1 genes were significantly different. These data suggest an association between the IVS2+31G>A SNP of the OPRM1 gene and pressure pain sensitivity in healthy adult females.
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PMID:Association between human opioid receptor genes polymorphisms and pressure pain sensitivity in females*. 1903 94

The opioidergic system, an endogenous stress pathway, modulates cardiac function. Furthermore, opioid peptide and receptor expression is altered in a number of cardiac pathologies. However, whether the response of myocardial opioid receptor signaling is altered in heart failure progression is currently unknown. Elucidating possible alterations in and effects of opioidergic signaling in the failing myocardium is of critical importance as opioids are commonly used for pain management, including in patients at risk for cardiovascular disease. A hamster model of cardiomyopathy and heart failure (Bio14.6) was used to investigate cardiac opioidergic signaling in heart failure development. This study found an augmented negative inotropic and lusitropic response to administration of agonists selective for the kappa opioid receptor and delta opioid receptor in the failing heart that was mediated by a pertussis toxin-sensitive G-protein. The augmented decrease in cardiac function was manifested by increased inhibition of cAMP accumulation and the amplitude of the systolic Ca(2+) transient. Furthermore, increased depression of cardiac function and of two important second messengers, cAMP and intracellular Ca(2+), were independent of changes in cardiac opioid peptide or receptor expression. Thus, the cardiomyopathy-induced failing heart experiences increased cardiac depressant effects following opioid receptor stimulation which could exacerbate diminished cardiac function in end-stage heart failure. As cardiac function is already depressed in heart failure patients, administration of opioids could exacerbate the degree of cardiac dysfunction and worsen disease progression.
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PMID:Kappa and delta opioid receptor signaling is augmented in the failing heart. 1957 31

Similar to mu opioid receptors, kappa and delta opioid receptors reside in the periphery, the dorsal root ganglion, the spinal cord, and in supraspinal regions associated with pain modulation. Both delta and kappa opioid agonists have been shown to activate pain inhibitory pathways in the central nervous system. Yet, currently there are only a few pharmacologic agents that target kappa receptors, and none that target delta receptors. Spurred by the need for an efficacious analgesic without the unwanted side effects associated with the typical clinical profile of mu opioid agonists, new research has provided insight into why the development of effective kappa and delta opioid receptor agonists has remained elusive thus far, and importantly, how these obstacles may be overcome. For example, for delta opioid agonists to be effective, a state of inflammation may be required as this induces delta opioid receptors to migrate to the surface of neuronal cells and thereby become accessible to delta opioid agonists. Studies have shown that delta opioid agonists can provide relief of inflammatory pain and malignant bone pain. Meanwhile, peripherally restricted kappa opioid agonists have been developed to target kappa opioid receptors located on visceral and somatic afferent nerves for relief of inflammatory, visceral, and neuropathic chronic pain. The recently shown efficacy of these analgesics combined with a possible lower abuse potential and side effect burden than mu opioid receptor agonists makes delta and peripherally restricted kappa opioid receptor agonists promising targets for treating pain.
Clin J Pain 2010 Jan
PMID:Delta and kappa opioid receptors as suitable drug targets for pain. 2002 60


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