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)

We have previously reported that ischemic spinal cord injury in rats leads to chronic pain-related behaviors. Thus, rats exhibited aversive reactions to innocuous mechanical stimuli (mechanical allodynia) applied to a body area at or rostral to the dermatomes innervated by the injured spinal segments. The responses of the rats to cold are also markedly enhanced (cold allodynia). Interestingly, more than 50% of spinally injured rats did not develop these abnormal pain-related behaviors after spinal cord injury. In the present study, we showed that the extent of injury is similar between allodynic and non-allodynic rats. Furthermore, intrathecal (i.t.) naloxone, a broad-spectrum opioid receptor antagonist, reversibly provoked mechanical and cold allodynia-like responses in spinally injured rats that did not develop such behaviors spontaneously. However, naloxone did not elicit such reactions in normal rats and did not alter the tail-flick latency in normal or spinally injured rats. Furthermore, i.t. D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) or naltridole, selective antagonists of mu and delta opioid receptors, respectively, also triggered pain-related behaviors similarly to naloxone. Although norbinaltorphimine (nor-BIN), a selective kappa-receptor antagonist, also elicited such responses, the time course of the effect makes it unlikely that spinal kappa-receptors were involved. These results suggested that the expression of abnormal pain-related behaviors in some spinally injured rats is tonically suppressed by the spinal opioidergic system. Interindividual differences that lead to lack or dysfunction of such inhibition may underly the appearence of pain-related behavior in some, but not all, spinally injured rats. It is suggested that such inhibition is exerted through spinal mu and delta, but not kappa, opioid receptors. The endogenous opioidergic control appears to be only active against abnormal painrelated behaviors in spinally injured rats. Our results are relevant for the clinical observation that only a subgroup of patients with nerve injury suffers from neuropathic pain.
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PMID:Evidence that spinal endogenous opioidergic systems control the expression of chronic pain-related behaviors in spinally injured rats. 954 96

We examined the effects of intrathecal (i.t.) selective opioid receptor agonists in alleviating mechanical and cold allodynia in spinally injured rats. Both DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, a mu-opioid receptor agonist) and DPDPE ([D-Phe2,D-Phe5]-enkephalin, a delta-opioid receptor agonist) dose-dependently relieved the chronic allodynia-like behavior at doses selective for their respective receptors. The anti-allodynic effect of DAMGO and DPDPE was reversed by the selective mu- and delta-opioid receptor antagonists CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) and naltrindole, respectively. In contrast, the selective kappa-opioid receptor agonist U50488H did not alleviate the allodynia-like behavior, but rather enhanced it. The anti-nociceptive and anti-allodynic effect of i.t. DAMGO was blocked by U50488H. Thus, activation of spinal mu- and delta-, but not kappa-opioid receptors produced anti-allodynic effect in this model of central pain. Drugs which act selectively on opioid receptor subtypes may be useful in managing chronic central pain of spinal cord origin.
Pain 1998 Apr
PMID:Treatment of chronic allodynia in spinally injured rats: effects of intrathecal selective opioid receptor agonists. 958 56

Inhibition of aminopeptidase N and neutral endopeptidase-24.11, two zinc metallopeptidases involved in the inactivation of the opioid peptides enkephalins, produces potent physiological analgesic responses, without major side-effects, in all animal models of pain in which morphine is active. Dual inhibitors of both enzymes could fill the gap between opioid analgesics and antalgics. Until now, attempts to find a compound with high affinity both for neutral endopeptidase and aminopeptidase N have failed. We report here the design of dual competitive inhibitors of both enzymes with KI values in the nanomolar range. These have been obtained by selecting R1, R2, and R3 determinants in aminophosphinic-containing inhibitors: NH2---CH(R1)P(O)---(OH)CH2---CH(R2)CONH---CH(R3)COOH, for optimal recognition of the two enkephalin inactivating enzymes, whose active site peculiarities, determined by site-directed mutagenesis, have been taken into account. The best inhibitors were 10x more potent than described dual inhibitors in alleviating acute and inflammatory nociceptive stimuli in mice, thus providing a basis for the development of a family of analgesics devoid of opioid side effects.
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PMID:Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: a class of central analgesics. 975 84

The modulatory effects of 1DMe (d-Tyr-Leu-(NMe)Phe-Gln-Pro-Gln-Arg-Phe-NH2), an agonist of Neuropeptide FF (NPFF) receptors, on opioid antinociceptive activity have been compared in naive and tolerant mice in the tail-flick and the hot-plate tests. In naive mice, 1DMe alone had no effect on pain threshold but decreased dose-dependently (3-22 nmol) the analgesic activity of morphine in both tests. In tolerant mice, injections of 60-fold lower doses of 1DMe (0.05-0.5 nmol) reverse morphine-induced analgesia in the tail-flick test but this anti-opioid effect was no longer observed with the highest doses of 1DMe tested (3-22 nmol). In the hot-plate test, the anti-opioid action of 1DMe was not detected, whatever doses tested. Neither the NPFF-like immunoreactivity content of spinal cord and of olfactory bulbs, nor the density of NPFF receptors in olfactory bulbs, were altered. These results indicate that a chronic morphine treatment modifies the pharmacological properties of NPFF but the type of pain test is crucial in determining NPFF effects.
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PMID:Anti-opioid efficacy of neuropeptide FF in morphine-tolerant mice. 976 58

The contribution of a peripheral action of the kappa-opioid receptor agonist U-69,593 (trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl) cycloexil] benzene-acetamide methanesulfonate) in the augmented antinociceptive effect of this substance was investigated in a well-established rat model of peripheral unilateral neuropathy (chronic constriction of the common sciatic nerve). Relatively low dose of systemic U-69,593 (0.75 mg/kg intravenous (i.v.)) and intraplantar (i.pl.) low doses of specific antagonists of kappa-(nor-binaltorphimine) or mu-(D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2: CTOP) opioid receptors were used. Vocalization thresholds to paw pressure were used as a nociceptive test. The i.pl. injection of nor-binaltorphimine (10-15 microg injected into the nerve-injured hind paw) had no effect on the antinociceptive effect of U-69,593. Higher doses (20-30 microg i.pl. nor-binaltorphimine) significantly reduced the effect of U-69,593 on this paw but not on the contralateral paw, an effect which plateaued at 30 microg. By contrast, the i.pl. injection of CTOP (1 microg into the nerve-injured paw) had no effect on U-69,593 antinociception, whereas it reduced the effect of systemic morphine in these animals. The doses of nor-binaltorphimine used, injected into the contralateral paw or i.v., failed to modify the antinociceptive effects of U-69,593 on either paw. These results provide evidence for a peripheral component in the enhanced antinociceptive effect of systemic U-69,593 in this model of neuropathic pain.
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PMID:Peripheral component in the enhanced antinociceptive effect of systemic U-69,593, a kappa-opioid receptor agonist in mononeuropathic rats. 979 33

Nociceptin (orphanin FQ), the newly discovered endogenous ligand for the novel opioid receptor-like 1 receptor, has been initially found to participate in pain modulation. In this study, centrally mediated cardiovascular actions of this peptide were investigated in the alpha-chloralose/urethane-anesthetized rats. We found that bilateral injection of nociceptin (10 nmol) into the rostral ventrolateral medulla (RVLM), wherein injection of excitatory amino acid dl-homocysteic acid (3 nmol) induced typical pressor responses, significantly reduced arterial blood pressure and heart rate by -32% and -15%, respectively. Reduction of blood pressure and heart rate in response to intra-RVLM injection of nociceptin was dose-dependent with a threshold dose being 3 nmol. Pretreatment with the selective nociceptin receptor antagonist, [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 (10 nmol), into the RVLM abolished the nociceptin-induced cardiovascular inhibition. In contrast, non-selective opioid receptor antagonist, naloxone (10 nmol), did not modify the hypotension and bradycardia induced by nociceptin, even though naloxone at the same dose prevented reduction of blood pressure and heart rate induced by intra-RVLM injection of methionine-enkephalin (3 nmol). Both [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 and naloxone injection alone had no significant effect on baseline blood pressure and heart rate. These data suggest that the newly discovered opioid-like neuropeptide nociceptin in the CNS exert powerful influence on hemodynamic activity by affecting the RVLM neurons. This influence is inhibitory in nature, which may not be active in normal physiological conditions. Moreover, the cardiovascular effects of nociceptin were mediated by activation of specific nociceptin receptors rather than typical naloxone-sensitive opioid receptors.
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PMID:Inhibition of cardiovascular activity following microinjection of novel opioid-like neuropeptide nociceptin (orphanin FQ) into the rat rostral ventrolateral medulla. 1035 May 39

1 Stimulation of the opioid receptor-like1 (ORL-1) receptor by nociceptin (NC) produces hyperalgesia and reverses the antinociceptive effects induced by opioids. Most studies concerning the central effects of NC were conducted using acute pain models. The role NC may play in chronic inflammation remains unelucidated. 2 The present study was undertaken to assess the action of NC in the Freund's adjuvant-induced monoarthritic rat model. The effects of drugs known to act as analgesics in this model were evaluated. The effects of NC, NCNH2, and the ORL-1 ligand, [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 ([F/G]NC(1-13)NH2), were also studied alone or in association with morphine. 3 NC (1 - 30 nmol, i. c.v.) was inactive, whilst NCNH2 (10 nmol, i.c.v.) exerted hyperalgesic effects (-4.5+/-0.9 vs -0.7+/-0.8 s of vehicle-treated animals). [F/G]NC(1-13)NH2 (0.01 - 10 nmol, i.c.v.) induced hyperalgesia in the arthritic paw (-3.3+/-0.6 vs -0.3+/-0.5 s of vehicle-treated animals; 10 nmol). 4 Both NC (0.01 - 10 nmol, i.c.v. ) and [F/G]NC(1-13)NH2 (0.01 - 1 nmol, i.c.v), 30 min after morphine (3 mg kg-1, s.c.) induced an immediate and short-lived reversal of morphine effects (2.6+/-0.3 vs 10.4+/-1.0 and 1.2+/-1.5 vs 9.3+/-1.1 s of morphine alone, respectively), therefore displaying anti-opioid activity. 5 In the Freund's adjuvant-induced rat model of arthritis, both NC and [F/G]NC(1-13)NH2 act as anti-opioid peptides. Furthermore, NCNH2 and [F/G]NC(1-13)NH2 induce hyperalgesia when given alone. Further investigations and the identification of a centrally acting ORL-1 antagonist are necessary to better understand the role of NC in pain mechanisms.
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PMID:Nociceptin and the ORL-1 ligand [Phe1psi (CH2-NH)Gly2]nociceptin(1-13)NH2 exert anti-opioid effects in the Freund's adjuvant-induced arthritic rat model of chronic pain. 1057 39

Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2) are peptides recently isolated from brain that show the highest affinity and selectivity for the mu (morphine) opiate receptor of all the known endogenous opioids. The endomorphins have potent analgesic and gastrointestinal effects. At the cellular level, they activate G-proteins (35S-GTP gamma-S binding) and inhibit calcium currents. Support for their role as endogenous ligands for the mu-opiate receptor includes their localization by radioimmunoassay and immunocytochemistry in central nervous system regions of high mu receptor density. Intense EM-2 immunoreactivity is present in the terminal regions of primary afferent neurons in the dorsal horn of the spinal cord and in the medulla near high densities of mu receptors. Chemical (capsaicin) and surgical (rhizotomy) disruption of nociceptive primary afferent neurons depletes the immunoreactivity, implicating the primary afferents as the source of EM-2. Thus, EM-2 is well-positioned to serve as an endogenous modulator of pain in its earliest stages of perception. In contrast to EM-2, which is more prevalent in the spinal cord and lower brainstem, EM-1 is more widely and densely distributed throughout the brain than EM-2. The distribution is consistent with a role for the peptides in the modulation of diverse functions, including autonomic, neuroendocrine, and reward functions as well as modulation of responses to pain and stress.
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PMID:Endomorphins: novel endogenous mu-opiate receptor agonists in regions of high mu-opiate receptor density. 1067 42

A novel opioid receptor-like orphan receptor (ORL1) was cloned and identified to be homologous to classical opioid receptors but insensitive to traditional opioids. A heptadecapeptide, termed orphanin FQ or nociceptin (OFQ/N), was identified as its endogenous ligand. OFQ/N shares overlapping distribution sites in pain-processing areas and common cellular mechanisms with opioids but exerts diverse effects on nociceptive responses. Of the two reported ORL1 antagonists, [Phe(1)psi(CH(2)-NH)- Gly(2)] nociceptin-(1-13)-NH(2) (Phepsi) and naloxone benzoylhydrazone (NBZ), antagonisms were validated in the activation of inward rectifying K channels induced by OFQ/N, using the patch clamp technique in ventrolateral periaqueductal gray slices. Results showed that Phepsi acted as a partial agonist and NBZ was a weak nonselective antagonist of ORL1. It is comparable with most but not all of the findings from other tissues. Comparing all the reports supports the above inference for these two antagonists. The possible causes for the discrepancy were discussed. A brief review on the putative ORL1 antagonists, acetyl-RYYRIK-NH2, some sigma-ligands and the functional antagonist, nocistatin, is also included. It indicates that a potent and selective ORL1 antagonist is expecting to elucidate the physiological role of OFQ/N.
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PMID:Pharmacological characterization of the nociceptin receptor, ORL1. Insight from the inward rectifier activation in the periaqueductal gray. 1081 Feb 42

Patients with reflex sympathetic dystrophy have posttraumatic pain disproportionate to the injury and spreading beyond the distribution of any single peripheral nerve. We examined sympathetic neurocirculatory function and the role of sympathetic postganglionic nerve traffic in maintaining the pain in 30 patients with reflex sympathetic dystrophy. Most had had the condition for more than 1 year, and 14 had undergone sympathectomy for the pain. Positron emission tomographic scanning after administration of 13N-ammonia was used to assess local perfusion, and 6-[18F]fluorodopamine was used to assess sympathetic innervation. Rates of entry of norepinephrine in the regional venous drainage (spillovers) and regional plasma levels of L-dihydroxyphenylalanine (the immediate product of the rate-limiting enzymatic step in norepinephrine biosynthesis) and dihydroxyphenylglycol (the main neuronal metabolite of norepinephrine) were measured with and without intravenous trimethaphan for ganglion blockade. 13N-Ammonia-derived radioactivity was less on the affected side than on the unaffected side, whereas 6-[18F]fluorodopamine-derived radioactivity was symmetrical. Thus, perfusion-adjusted 6-[18F]fluorodopamine-derived radioactivity was higher on the affected side. Norepinephrine spillover and arteriovenous increments in plasma levels of L-dihydroxyphenylalanine and dihydroxyphenylglycol did not differ significantly between affected and unaffected limbs, although 4 patients had noticeably less norepinephrine spillover and smaller arteriovenous increments in plasma dihydroxyphenylglycol on the affected side. Trimethaphan decreased the pain in only 2 of 12 nonsympathectomized patients. The results indicate that patients with chronic unilateral reflex sympathetic dystrophy have decreased perfusion of the affected limb, symmetrical sympathetic innervation and norepinephrine synthesis, variably decreased release and turnover of norepinephrine in the affected limb, and failure of ganglion blockade to improve the pain in most cases. These findings suggest augmented vasoconstriction, intact sympathetic terminal innervation, possibly impaired sympathetic neurotransmission, and pain usually independent of sympathetic neurocirculatory outflows.
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PMID:Sympathetic innervation and function in reflex sympathetic dystrophy. 1089 15


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