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

Administration of capsaicin (8-methyl-N-vanillyl-6-nonenamide) to neonatal rats gives a long-lasting insensitivity to chemical irritants, and its potential as a specific toxin for peripheral C-fibers has made it of particular interest to neurobiologists concerned with pain mechanisms. The existence of capsaicin receptor on primary afferent sensory neurons is now evident. To deduce a receptor model for capsaicin, and propose the possible molecular interactions at the site of action, we prepared more than 50 capsaicin congeners (capsaicinoids). With these capsaicinoids, we investigated the role of functional groups in producing the long-lasting analgesia by phenylquinone writhing test and Randall-Selitto's method with ICR mice and SD rats. The structure-activity relationship of capsaicin in producing analgesia was established as follows: proper length of hydrophobic alkyl chain is 8-18 carbon atoms; 3-methoxy group of aromatic ring plays an important role but not essential; the presence of phenolic-OH is indispensable and the most suitable site is para-position; acyl amide linkage is dispensable; the linkage of amide bond bridged to the ring with CH2 is appropriate. Depletion of substance P from spinal cord and dorsal horn of rats by capsaicinoids was proved by RIA and immunohistochemistry. We succeeded in eliminating a potent acute toxicity shown by capsaicin through its structural modification.
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PMID:Neurotoxicity and long lasting analgesia induced by capsaicinoids. 192 May 42

A personal opinion on the way analgesia should be piloted in labour is expressed and reference is made to personal results with continuous venous drip perfusion of ketamin with a SIC P77 infusional pump in 110 cases. The data from the series are described and particular attention is given to the behaviour of the drug with respect to uterine dynamics and the incidence of instrumental intervention. Stress is laid on the considerable benefits offered by the method, including reduction of the labour period and good maternal and foetal tolerance.
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PMID:[Analgesia in labor with continuous--drip venous perfusion of ketamine]. 724 65

It is well established that the vanilloid receptor, VR1, is an important peripheral mediator of nociception. VR1 receptors are also located in several brain regions, yet it is uncertain whether these supraspinal VR1 receptors have any influence on the nociceptive system. To investigate a possible nociceptive role for supraspinal VR1 receptors, capsaicin (10 nmol in 0.4 microl) was microinjected into either the dorsal (dPAG) or ventral (vPAG) regions of the periaqueductal gray. Capsaicin-related effects on tail flick latency (immersion in 52 degrees C water) and on neuronal activity (on-, off-, and neutral cells) in the rostral ventromedial medulla (RVM) were measured in lightly anesthetized rats. Administration of capsaicin into the dPAG but not the vPAG caused an initial hyperalgesic response followed later by analgesia (125 +/- 20.96 min postinjection). The tail flick-related burst in on-cell activity was triggered earlier in the hyperalgesic phase and was delayed or absent during the analgesic phase. Spontaneous activity of on-cells increased at the onset of the hyperalgesic phase and decreased before and during the analgesic phase. The tail flick-related pause in off-cell activity as well as spontaneous firing for these cells was unchanged in the hyperalgesic phase. During the analgesic phase, off-cells no longer paused during noxious stimulation and had increased levels of spontaneous activity. Neutral cell firing was unaffected in either phase. Pretreatment with the VR1 receptor antagonist, capsazepine (10 nmol in 0.4 microl), into the dPAG blocked the capsaicin-induced hyperalgesia as well as the corresponding changes in on- and off-cell activity. VR1 receptor immunostaining was observed in the dPAG of untreated rats. Microinjection of capsaicin likely sensitized and then desensitized dPAG neurons affecting nocifensive reflexes and RVM neuronal activity. These results suggest that supraspinal VR1 receptors in the dPAG contribute to descending modulation of nociception.
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PMID:Capsaicin infused into the PAG affects rat tail flick responses to noxious heat and alters neuronal firing in the RVM. 1281 18

Capsaicin causes pain by activating VR1, a cloned capsaicin receptor, in sensory neurons. After the initial excitatory responses, capsaicin produces prolonged analgesia, presumably because of the neurotoxic effect that leads to the death of sensory neurons. However, the mechanism underlying capsaicin-induced cell death of sensory neurons is not known. Here we report that capsaicin induces cell death in VR1-expressing sensory neurons and VR1-transfected human embryonic kidney cells. Cell death of sensory neurons induced by capsaicin is accompanied by DNA fragmentation, TUNEL staining, and shrinkage of the nucleus in a caspase-dependent manner, indicating the apoptotic nature of the cell death. Mitochondrial permeability transition is likely to be a major component of capsaicin-induced cell death because bonkrekic acid and cyclosporin A, inhibitors of mitochondrial permeability transition, block this cell death. These results imply that capsaicin induces mitochondrial dysfunction in VR1-expressing cells, leading to apoptotic cell death, which is a well-known neurotoxic effect of capsaicin.
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PMID:Essential role of mitochondrial permeability transition in vanilloid receptor 1-dependent cell death of sensory neurons. 1455 Jul 68

Vanilloid receptor 1 (TRPV1), a nonspecific cation channel expressed primarily in small sensory neurons, mediates inflammatory thermal pain sensation. The function and expression of TRPV1 are enhanced during inflammation and certain neuropathies, leading to sustained hyperalgesia. Activation of TRPV1 in the spinal cord and periphery promotes release of adenosine, which produces analgesia by activating A(1) and A(2A) adenosine receptor (AR) on central and peripheral neurons. This study provides evidence of a direct interaction of AR analogs with TRPV1. Adenosine analogs inhibit TRPV1-mediated Ca(2+) entry in human embryonic kidney (HEK293) cells stably expressing TRPV1 (HEK/TRPV1) and DRG neurons. This inhibition was independent of A(2A)AR activation. Specific binding of [(3)H]resiniferatoxin (RTX) in plasma membrane preparations was inhibited by CGS21680, an A(2A)AR agonist. Similar degrees of inhibition were observed with both agonists and antagonists of ARs. Adenosine analogs inhibited [(3)H]RTX binding to affinity-purified TRPV1, indicative of a direct interaction of these ligands with the receptor. Furthermore, specific capsaicin-sensitive binding of [(3)H]CGS21680 was observed in Xenopus oocyte membranes expressing TRPV1. Capsaicin-induced inward currents in DRG neurons were inhibited by adenosine and agonist and antagonist of A(2A)AR at nanomolar concentrations. Increasing the concentrations of capsaicin reversed the inhibitory response to capsaicin, suggesting a competitive inhibition at TRPV1. Finally, exposure of HEK/TRPV1 cells to capsaicin induced an approximately 2.4-fold increase in proapoptotic cells that was abolished by adenosine analogs. Together, these data suggest that adenosine could serve as an endogenous inhibitor of TRPV1 activity by directly interacting with the receptor protein.
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PMID:Direct interaction of adenosine with the TRPV1 channel protein. 1507 Nov 15

Control of cancer, neuropathic, and postoperative pain is frequently inadequate or compromised by debilitating side effects. Inhibition or removal of certain nociceptive neurons, while retaining all other sensory modalities and motor function, would represent a new therapeutic approach to control severe pain. The enriched expression of transient receptor potential cation channel, subfamily V, member 1 (TRPV1; also known as the vanilloid receptor, VR1) in nociceptive neurons of the dorsal root and trigeminal ganglia allowed us to test this concept. Administration of the potent TRPV1 agonist resiniferatoxin (RTX) to neuronal perikarya induces calcium cytotoxicity by opening the TRPV1 ion channel and selectively ablates nociceptive neurons. This treatment blocks experimental inflammatory hyperalgesia and neurogenic inflammation in rats and naturally occurring cancer and debilitating arthritic pain in dogs. Sensations of touch, proprioception, and high-threshold mechanosensitive nociception, as well as locomotor function, remained intact in both species. In separate experiments directed at postoperative pain control, subcutaneous administration of RTX transiently disrupted nociceptive nerve endings, yielding reversible analgesia. In human dorsal root ganglion cultures, RTX induced a prolonged increase in intracellular calcium in vanilloid-sensitive neurons, while leaving other, adjacent neurons unaffected. The results suggest that nociceptive neuronal or nerve terminal deletion will be effective and broadly applicable as strategies for pain management.
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PMID:Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control. 1512 26

Vanilloid receptor 1 (TRPV1) is a Ca2+ permeable non-specific cation channel located at the peripheral nerve terminals and functions as a polymodal nociceptor. Neomycin, an aminoglycoside antibiotic induces analgesia in various animal models. However, the mechanism of action of neomycin has not been fully understood. In this study, we have determined the effect of neomycin on native TRPV1 in cultured embryonic DRG neurons and cloned TRPV1 heterologously expressed in Xenopus oocytes using patch clamp, double electrode voltage clamp, and Ca2+ fluorescence imaging techniques. Here, we show that neomycin potently (IC50 approximately 400 nM) blocks TRPV1-mediated membrane currents in DRG neurons and the block is unrelated to capsaicin concentrations used to evoke currents, suggesting a non-competitive block. Similarly, capsaicin- and proton-induced currents are blocked in oocytes, but to a lesser extent. Increases in capsaicin-induced intracellular Ca2+ levels are also reduced by neomycin. Single-channel current analyses reveal that single-channel conductance is unaffected by neomycin and there is no indication of open channel block. The predominant effect is to lower, the open probability (Po) at both, negative and positive potentials. Kinetic analyses reveal that the number of exponential components required to fit the open time distributions remains the same or reduced, however, the longest open time constant and the area of distribution are shortened at negative and positive potentials, respectively. The area of distribution of longest closed-time constants were significantly prolonged at negative and positive potentials. We conclude that neomycin inhibits TRPV1 channel activity by allosteric binding and altering channel gating.
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PMID:Block of native and cloned vanilloid receptor 1 (TRPV1) by aminoglycoside antibiotics. 1562 72

The intra-plantar acute administration of 10 microg of capsaicin to mice which had received complete Freund's adjuvant (CFA) 1 week before inhibits the thermal inflammatory hyperalgesia it induces and even produces a long-lasting analgesia for at least 2 weeks. In this study, we show that the administration of capsaicin (10 microg) also reduces the immediate licking behavior evoked by the intra-plantar administration of a lower dose of capsaicin (0.1 microg), the duration of this inhibitory effect being greater in CFA-inflamed mice (at least 2 weeks) than in non-inflamed animals (less than 4 days). Since this reduction of capsaicin-induced licking behavior may be interpreted as a consequence of the transient receptor potential vanilloid 1 receptor (TRPV1) unresponsiveness, we conclude that the administration of 10 microg of capsaicin into inflamed tissues can render the TRPV1 desensitised. We next explored whether endogenous vanilloids released during inflammation contribute to maintain the analgesia triggered by exogenous capsaicin. The acute administration of capsazepine (10 microg; intra-plantarly (i.pl.)) abolished the analgesic effect induced by the injection of capsaicin 1 week before in inflamed mice. From these results, it may be proposed that the maintenance by endovanilloids of the TRPV1 desensitisation induced by capsaicin could contribute to prolonging the analgesic effect induced by this agonist in inflamed tissues.
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PMID:TRPV1 desensitisation and endogenous vanilloid involvement in the enhanced analgesia induced by capsaicin in inflamed tissues. 1621 96

Anandamide, the ethanolamide of arachidonic acid, is an endogenous cannabinoid. It is an agonist at CB1 and CB2 cannabinoid receptors as well as the vanilloid receptor, VR1. It is analgesic in inflammatory and neuropathic pain. Both central and peripheral mechanisms are considered to participate in its analgesia. Primary sensory neurons express Na+ currents that are involved in the pathogenesis of pain. We examined the effect of anandamide on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na+ currents in rat dorsal root ganglion neurons. Anandamide inhibited both Na+ currents in a concentration-dependent manner. At a membrane potential of -80 mV, the current inhibition was greater in TTX-S than TTX-R currents (K(d); 5.4 microM vs. 38.4 microM). The activation and inactivation became faster in TTX-R current but not in TTX-S current. Anandamide did not alter the activation voltage in either type of current. It, however, produced a hyperpolarizing shift of the steady-state inactivation voltage in both types of currents. The maximum availability at a large negative potential was not reduced by anandamide. Thus, anandamide seems to affect inactivated Na+ channels rather than resting channels. The inhibition of Na+ currents was not reversed by AM 251 (a CB1 antagonist), AM 630 (a CB2 antagonist) or capsazepine (a VR1 antagonist), suggestive of a direct action of anandamide on Na+ channels. The inhibition of Na+ currents in sensory neurons may contribute to the anandamide analgesia.
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PMID:Anandamide suppression of Na+ currents in rat dorsal root ganglion neurons. 1625 60

Capsaicinoids are botanical irritants present in chili peppers. Chili pepper extracts and capsaicinoids are common dietary constituents and important pharmaceutical agents. Use of these substances in modern consumer products and medicinal preparations occurs worldwide. Capsaicinoids are the principals of pepper spray self-defense weapons and several over-the-counter pain treatments as well as the active component of many dietary supplements. Capsaicinoids interact with the capsaicin receptor (a.k.a., VR1 or TRPV1) to produce acute pain and cough as well as long-term analgesia. Capsaicinoids are also toxic to many cells via TRPV1-dependent and independent mechanisms. Chemical modifications to capsaicinoids by P450 enzymes decreases their potency at TRPV1 and reduces the pharmacological and toxicological phenomena associated with TRPV1 stimulation. Metabolism of capsaicinoids by P450 enzymes also produces reactive electrophiles capable of modifying biological macromolecules. This review highlights data describing specific mechanisms by which P450 enzymes convert the capsaicinoids to novel products and explores the relationship between capsaicinoid metabolism and its effects on capsaicinoid pharmacology and toxicology.
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PMID:Metabolism of capsaicinoids by P450 enzymes: a review of recent findings on reaction mechanisms, bio-activation, and detoxification processes. 1714 96


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