Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Following transection of the optic nerve (ON) in the adult rat, 85% of axotomized retinal ganglion cells (RGCs) undergo degeneration within 14 days. Here, we examined the effects of various anesthetic and analgesic compounds on the number of RGCs surviving ON lesion. Five different protocols for rodent anesthesia were used (A, chloral hydrate; B, chloral hydrate/carprofen; C, chloral hydrate/buprenorphine; D, ketamine/xylazine; E, fentanyl/medetomidin/midazolam), and the numbers of RGCs surviving 14 days after ON axotomy were compared to evaluate if the agents used may affect numbers of surviving RGCs. In many laboratories, rodent ON surgery is performed with chloral hydrate anesthesia, and this condition was used as baseline, with 343.7 +/- 29.1 RGCs/mm(2) surviving after 14 days. The addition of carprofen to chloral hydrate did not affect RGC numbers (382.7 +/- 15.2 RGCs/mm(2); n.s.), while chloral hydrate with buprenorphine (421.1 +/- 25.1 RGCs/mm(2); p < 0.05), ketamine and xylazine (403.6 +/- 36.1 RGCs/mm(2); p < 0.05), or fentanyl with medetomidine and midazolam (481.3 +/- 10.4 RGCs/mm(2); p < 0.05) all increased RGC survival. In a second series of experiments, ON axotomized rats were treated with an adenoviral vector expressing GDNF (Ad.GDNF) that rescues injured RGCs, to study if the anesthetics (A, B, E; see above) would influence the degree of RGC neuroprotection afforded by GDNF. Intravitreal injection of Ad.GDNF at a low titre rescued approximately 10% of RGCs that would have degenerated without treatment using either of the three different anesthesia protocols, yet GDNF did not exert synergistic neuroprotection with any of the anesthetics tested. Our results indicate that in combination carprofen and chloral hydrate, while affording safe and reliable anesthesia and analgesia for rat ON surgery, does not affect the numbers of surviving RGCs. Therefore, data obtained with this combination may be related to experimental data obtained previously with only chloral hydrate anesthesia. All other protocols afforded some degree of RGC neuroprotection that may be utilized for experimental therapies of neurodegeneration, yet needs to be taken into careful consideration when mechanisms of neurodegeneration or approaches towards neuroprotection of RGCs are examined.
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PMID:Neuroprotective properties of different anesthetics on axotomized rat retinal ganglion cells in vivo. 1498 67

Sensitization to mechanical stimuli is important in most pain syndromes. We evaluated the populations of nociceptors mediating mechanical hyperalgesia and those mediating mu-opioid receptor (MOR) and delta-opioid receptor (DOR) agonist-induced inhibition of hyperalgesia, in the rat. We found that: (1) intradermal injection of both the endogenous ligand for the Ret receptor, glia-derived growth factor (GDNF), and the ligand for the tropomyosin receptor kinase A (TrkA) receptor, nerve growth factor (NGF)-which are present on distinct populations of nociceptors-both produce mechanical hyperalgesia; (2) DOR agonist 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide (SNC) but not MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) inhibit GDNF-induced hyperalgesia; (3) both DAMGO and SNC inhibit NGF hyperalgesia, even in rats pretreated with isolectin B4 (IB4)-saporin, a toxin that destroys IB4-binding neurons; (4) co-administration of low doses of DAMGO and SNC produce enhanced analgesia, and; (5) repeated administration of DAMGO produces cross-tolerance to the analgesic effect of SNC. These findings demonstrate that, most nociceptors have a role in mechanical hyperalgesia, only the DOR agonist inhibits GDNF hyperalgesia, and MOR and DOR are co-localized on a functionally important population of TrkA-positive nociceptors.
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PMID:Mu and delta opioid receptors on nociceptors attenuate mechanical hyperalgesia in rat. 2073 53

Human Hereditary Sensory Autonomic Neuropathies (HSANs) are characterized by insensitivity to pain, sometimes combined with self-mutilation. Strikingly, several sporting dog breeds are particularly affected by such neuropathies. Clinical signs appear in young puppies and consist of acral analgesia, with or without sudden intense licking, biting and severe self-mutilation of the feet, whereas proprioception, motor abilities and spinal reflexes remain intact. Through a Genome Wide Association Study (GWAS) with 24 affected and 30 unaffected sporting dogs using the Canine HD 170K SNP array (Illumina), we identified a 1.8 Mb homozygous locus on canine chromosome 4 (adj. p-val = 2.5x10-6). Targeted high-throughput sequencing of this locus in 4 affected and 4 unaffected dogs identified 478 variants. Only one variant perfectly segregated with the expected recessive inheritance in 300 sporting dogs of known clinical status, while it was never present in 900 unaffected dogs from 130 other breeds. This variant, located 90 kb upstream of the GDNF gene, a highly relevant neurotrophic factor candidate gene, lies in a long intergenic non-coding RNAs (lincRNA), GDNF-AS. Using human comparative genomic analysis, we observed that the canine variant maps onto an enhancer element. Quantitative RT-PCR of dorsal root ganglia RNAs of affected dogs showed a significant decrease of both GDNF mRNA and GDNF-AS expression levels (respectively 60% and 80%), as compared to unaffected dogs. We thus performed gel shift assays (EMSA) that reveal that the canine variant significantly alters the binding of regulatory elements. Altogether, these results allowed the identification in dogs of GDNF as a relevant candidate for human HSAN and insensitivity to pain, but also shed light on the regulation of GDNF transcription. Finally, such results allow proposing these sporting dog breeds as natural models for clinical trials with a double benefit for human and veterinary medicine.
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PMID:A Point Mutation in a lincRNA Upstream of GDNF Is Associated to a Canine Insensitivity to Pain: A Spontaneous Model for Human Sensory Neuropathies. 2803 18