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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue injury or the presence of foreign material initiates a series of pathophysiological events that may manifest as inflammatory pain. The physicochemical characteristics of the initiating factor trigger the release of a unique range of pain mediators that control the threshold and activation of nociceptors. It has been suggested that many nociceptors associated with inflammatory pain are dormant, and are activated by cyclo-oxygenase metabolites and sympathomimetic amines into a state of hyperalgesia. In this state, pain receptors may be activated by previously ineffective stimuli. The relative contribution of the mediators to the activation process varies with the experimental model or the pathophysiological process involved. The mechanisms that control the activity of the pain receptor are unfolding. Indeed, research has shown a central role for bradykinin (released from plasma) and cytokines (released from tissues and resident cells) in this process. The release of tumour necrosis factor-alpha (TNF-alpha) initiates the release of interleukin-1 and interleukin-8, which in turn liberate cyclo-oxygenase metabolites and sympathomimetic amines, respectively. In some models of inflammatory pain, bradykinin causes hyperalgesia via release of TNF-alpha. Drugs blocking cyclo-oxygenase (aspirin-like drugs), or those antagonising the effects of sympathomimetic amines (beta-blockers), prevent sensitisation of the pain receptors. However, during hyperalgesia only specific types of analgesics are capable of nociceptor downregulation. It is assumed that sensitisation of nociceptors is due to increased concentrations of cAMP/Ca++ in the sensory neurons. The effect of increased cAMP concentrations may be counteracted by stimulation of the arginine/nitric oxide/cGMP pathway. Peripherally acting opiates and dipyrone are examples of analgesics that act via this mechanism. The analgesic effects of glucocorticoids and nimesulide appear to be attributable to inhibition of cytokine release.
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PMID:The role of interleukins and nitric oxide in the mediation of inflammatory pain and its control by peripheral analgesics. 750 42

Once daily s.c. administration of 5 mg/kg morphine, a mu-opioid agonist, or U50488H (U50), a kappa 1-opioid agonist, for 5 days in male CD-1 mice results in a 2-3-fold shift to the right of the respective analgesic (tail flick) dose-response curves, indicating the development of tolerance. Concurrent s.c. administration of the competitive NMDA receptor antagonist, LY274614 (LY), at 24 mg/kg/24 h infusion (osmotic pump) or 6 mg/kg i.p. once daily attenuates the development of morphine tolerance, when the response to saline plus morphine is compared on day 5 with LY plus morphine. Using this paradigm, once daily administration of either the non-competitive NMDA antagonist, MK-801, at 0.3 mg/kg i.p. or the nitric oxide synthase inhibitor, NG-nitro-L-arginine (NorArg), at 1 mg/kg i.p. twice daily attenuated the development of morphine tolerance. None of these drugs modify the tail-flick response or alter the ED50 for morphine. In contrast, co-administration of LY, MK-801 or NorArg, as above, failed to attenuate the development of tolerance to U50 or to the kappa 3-opioid agonist, naloxone benzoylhydrazone (NalBzoH). These results suggest that mu-opioid tolerance but not kappa 1- or kappa 3-opioid tolerance involves the mediation of NMDA receptors and the nitric oxide system.
Pain 1994 Jan
PMID:The NMDA receptor antagonists, LY274614 and MK-801, and the nitric oxide synthase inhibitor, NG-nitro-L-arginine, attenuate analgesic tolerance to the mu-opioid morphine but not to kappa opioids. 751 9

Since nitric oxide (NO) has been implicated in nociceptive processing, the present study examined whether NO synthase inhibition with either Nw-nitro-L-arginine (L-NA) or its methyl ester (L-NAME) would alter antinociception elicited by either continuous (CCWS) or intermittent cold-water swims (ICWS) on the tail-flick and jump tests. Whereas CCWS antinociception on both tests was significantly potentiated by a dose range of L-NA (0.1-4 mg/kg IP) and L-NAME (1 mg/kg IP), ICWS antinociception was largely unaffected by these manipulations. In contrast, administration of the less active D isomer (D-NAME) failed to alter CCWS antinociception and reduced ICWS antinociception. The ability of NO synthase inhibition to potentiate CCWS antinociception could not be explained by changes in CCWS hypothermia. Since ICWS antinociception is mediated by mu-opioid manipulations and CCWS antinociception is sensitive to delta-opioid and nonopioid manipulations, this indicates that NO synthase inhibition may be acting upon a selective form of pain inhibition.
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PMID:Nitric oxide synthase inhibition selectively potentiates swim stress antinociception in rats. 751 79

The hypothesis tested was that inhibition of the L-arginine-nitric oxide (NO) pathway may represent a potential central mechanism of action for acetaminophen (paracetamol). Spinal administration of N-methyl-D-aspartate (NMDA, 0.5 nmol), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA, 0.1 nmol) or substance P (SP, 0.5 nmol) to the rat provoked a specific behaviour characterized by biting, scratching and licking (BSL). This behaviour was antagonized by pretreatment with acetaminophen for NMDA and SP but not for AMPA. Further, the antinociceptive effect of acetaminophen was readily reversed by administration of the natural substrate for nitric oxide synthase (NOS), L-arginine, but not by D-arginine. This suggests that the analgesic effect of acetaminophen is related to inhibition of NO generation. Potential mechanisms for this may involve NMDA and SP. Our data suggest that a significant portion of the analgesic effect of acetaminophen, when used clinically, may be related to an interaction with the central nervous system L-arginine-NO pathway.
Pain 1994 Jun
PMID:Acetaminophen blocks spinal hyperalgesia induced by NMDA and substance P. 752 8

The effects of a neuronal selective nitric oxide synthase (NOS) inhibitor, L-Ng-nitro arginine p-nitroanilide (L-Napna), upon the hyper-reflexia of a rat model of persistent visceral pain was investigated. A baseline cystometrogram (CMG) was performed by measuring intravesical pressure during vesical inflation. L-Napna (125-1000 micrograms) or vehicle (control) was then administered topically onto the exposed spinal cord, followed by another CMG. The bladder was then inflamed with turpentine and a final CMG performed. Neither L-Napna nor vehicle affected vesical reflexes in the absence of inflammation. However, following inflammation, a vesical hyper-reflexia was demonstrated in the control animals, which was prevented by L-Napna. Therefore, spinal NOS does not have a role in the generation of normal bladder reflexes, however it does modulate them during vesical inflammation.
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PMID:Topical spinal administration of a nitric oxide synthase inhibitor prevents the hyper-reflexia associated with a rat model of persistent visceral pain. 754 Feb 69

We recently reported that intrathecal (i.t.) administration of prostaglandin (PG) E2 or PGF2 alpha in conscious mice induced allodynia through a pathway that includes the glutamate receptor system. Allodynia induced by PGE2 and PGF2 alpha was blocked by antagonists for NMDA and metabotropic glutamate receptor subtypes, respectively. In the present study, we examined the possibility for the involvement of nitric oxide (NO) in the PG-evoked allodynia. Allodynia was assessed once every 5 min by light stroking of the flank of mice with a paintbrush. Intrathecal administration of L-arginine, a substrate of nitric oxide synthase (NOS), in conscious mice resulted in allodynia. Dose dependency of L-arginine for allodynia showed a bell-shaped pattern (1-10 micrograms/mouse). The maximal allodynic effect was observed with 5.0 micrograms at 10-15 min after i.t. injection, similar in time course and magnitude to that induced by L-glutamate. L-Arginine-induced allodynia was dose-dependently reduced by the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) and the soluble guanylate cyclase inhibitor methylene blue with IC50 values of 7.68 and 8.70 pg/mouse, respectively. PGE2-induced allodynia was also dose-dependently inhibited by L-NAME and methylene blue with IC50 values of 94.7 and 74.9 pg/mouse. PGF2 alpha-induced allodynia was inhibited by methylene blue with an IC50 value of 40.6 pg/mouse, but not by L-NAME at doses up to 1.0 ng.(ABSTRACT TRUNCATED AT 250 WORDS)
Pain 1995 May
PMID:Nitric oxide mediates allodynia induced by intrathecal administration of prostaglandin E2 or prostaglandin F2 alpha in conscious mice. 765 39

L-NG-nitro arginine p-nitroanilide (L-NAPNA), L-NG nitro arginine methyl ester (L-NAME) and L-NG-monomethyl arginine (L-NMMA) inhibit rat cerebellar nitric oxide synthase (NOS) with IC50s of 1.4 +/- 0.1 microM, 0.81 +/- 0.16 microM and 5.1 +/- 0.07 microM respectively. L-NAPNA inhibits the late phase of formalin-induced hindpaw licking (ED50, 57.2 mg kg-1) and acetic acid induced abdominal constrictions (ED50, 25 mg kg-1) in the mouse. L-NAPNA is approximately 65 times less active than L-NAME as an inhibitor of endothelium-dependent relaxation in the rabbit aorta and about 10 fold less potent as a vasopressor in the anaesthetized mouse. LNAPNA shows some degree of selectivity for the central NOS isoform and may be of clinical interest for the treatment of pain.
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PMID:L-NG-nitro arginine p-nitroanilide (L-NAPNA) is anti-nociceptive in the mouse. 768 56

The effect of intrathecal (i.t.) injection of the cytokine interferon-gamma) (IFN-gamma) on the spinal nociceptive flexor reflex was examined in decerebrate, spinalized, unanesthetized rats. IFN-gamma elicited an initial intense, brief facilitation of the flexor reflex followed by a sustained reflex facilitation lasting 40 +/- 5 min (range 20-65 min). The initial and prolonged reflex facilitations by IFN-gamma were partially and totally blocked, respectively, by i.t. pretreatment with nitro-L-arginine-ester, an inhibitor of nitric oxide synthase, at doses which did not influence spinal cord blood flow. Spinal application of IFN-gamma produced powerful and prolonged facilitation of the flexor reflex, possibly reflecting a hyperalgesic action of this cytokine. The facilitatory effect of IFN-gamma was mediated, at least in part, by the activation of the L-arginine-nitric oxide pathway. Thus, IFN-gamma released in the CNS may participate in eliciting pain and hyperalgesia in infectious or neuroinflammatory diseases where there is increased production of this cytokine.
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PMID:Intrathecal interferon-gamma facilitates the spinal nociceptive flexor reflex in the rat. 771 23

The involvement of spinal cord nitric oxide (NO) in the development of autotomy, a proposed behavioral model of denervation pain, was studied in sciatic and saphenous nerves transected rats injected intrathecally, 10-15 min prior to neurectomies, with NG-nitro-L-arginine methyl ester (L-NAME, 20-500 nmol), NG-nitro-D-arginine methyl ester (D-NAME, 500 nmol), L- or D-arginine (5 mumol), and 8-bromoguanosine 3':5'-cyclic monophosphate sodium salt (8-Br-cGMP, 100 and 200 nmol). Self-inflicted lesions were scored daily for 8 weeks. The main effects on autotomy were: (1) a significant suppression in rats injected with L-NAME (500 nmol), but not with D-NAME; (2) a significant potentiation after L-arginine, but not D-arginine; and (3) a significant potentiation with 8-Br-cGMP, which was blocked by co-administration of L-NAME. These findings indicate that autotomy in rats can be modulated by blocking or enhancing nitroxidergic transmission at lumbosacral level, and suggest new therapeutic approaches for the prevention of certain pain syndromes, such as phantom limb pain.
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PMID:Nitric oxide mediates neuropathic pain behavior in peripherally denervated rats. 778 79

A potential pathophysiological role for the urinary kallikrein-kinin system is suggested by the prominent symptoms of bladder pain and urinary frequency in interstitial cystitis. Kallikrein activity in the urine of 84 patients with interstitial cystitis and 33 normal volunteers was determined by cleavage of the synthetic substrate Val-Leu-Arg-pNA. Interstitial cystitis patients had significantly higher levels of kallikrein activity than did the normal volunteers. Kallikrein activity was correlated with symptoms of bladder pain and voiding frequency. The percentage of total urinary kallikrein in the active form correlated with active kallikrein levels and was also increased in interstitial cystitis patients, particularly those with higher levels of pain. Patients who underwent hydrodistention and subsequently experienced relief from the bladder symptoms had a decrease in urinary kallikrein levels, whereas patients who failed to improve following hydrodistention did not.
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PMID:Activation of urinary kallikrein in patients with interstitial cystitis. 805 40


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