Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162473 (Frey)
 2,599 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The actions of different cholinergic agonists and antagonists were investigated on nociceptive afferents using the rat skin-saphenous nerve preparation, in vitro. Nicotine was able to weakly excite C-nociceptors and to induce a mild sensitization to heat stimulation (in 77% of tested fibers) in a dose-dependent manner (10(-)6 to 10(-)5 m), but it caused no alteration in mechanical responsiveness tested with von Frey hairs. Muscarine did not induce a significant nociceptor excitation, but almost all fibers exhibited a marked desensitization to mechanical and heat stimuli in a dose-dependent manner (from 10(-)6 to 10(-)4 m). The muscarinic effects could be prevented by the general muscarinic antagonist scopolamine (10(-)5 m), by the M3 antagonist 1,1-dimethyl-4-diphenylacetoxypiperidium oxide (10(-)6 m) co-applied with the M2 antagonist gallamine (10(-)5 m), and by gallamine alone. As positive control we used the relatively M2-selective agonist arecaidine (10(-)6 to 10(-)5 m), obtaining a similar desensitizing effect as with muscarine. Finally, we performed an immunocytochemical study that demonstrated the presence of M2 but not M3 receptors in thin epidermal nerve fibers of the rat hairy skin. Altogether, these data demonstrate opposite effects of nicotinic and muscarinic receptor stimulation on cutaneous nociceptors. M2 receptor-mediated depression of nociceptive responsiveness may convey a therapeutic, i.e., analgesic or antinociceptive, potential.
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PMID:Excitatory nicotinic and desensitizing muscarinic (M2) effects on C-nociceptors in isolated rat skin. 1131 14

Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors can produce antinociception. However, the mechanisms of the action of cholinergic agents in the spinal cord are not fully understood. Activation of spinal muscarinic receptors evokes gamma-aminobutyric acid (GABA) release, which reduces the glutamatergic synaptic input to dorsal horn neurons through GABA(B) receptors. In this study, we determined the functional role of spinal GABA(B) receptors in the antinociceptive action of intrathecal cholinergic agents in normal rats and in a rat model of diabetic neuropathic pain. Diabetes was induced by intraperitoneal streptozotocin in rats. The intrathecal catheter was inserted with its tip positioned at the lumbar spinal level. Nociceptive threshold was measured by the paw withdrawal latency in response to a radiant heat stimulus in normal rats. Mechanical allodynia in diabetic rats was determined by von Frey filaments applied to the hindpaw. The effect of intrathecal muscarine or neostigmine was examined through pretreatment with the specific GABA(B) receptor antagonist, CGP55845, or its vehicle. Intrathecal injection of muscarine or neostigmine significantly increased the withdrawal latency in response to a heat stimulus in normal rats and the withdrawal threshold in response to application of von Frey filaments in diabetic rats. Intrathecal pretreatment with CGP55845 significantly attenuated the effect of both muscarine or neostigmine in normal rats. Furthermore, the antiallodynic effect of intrathecal neostigmine and muscarine was largely eliminated by CGP55845 in diabetic rats. These data suggest that the GABA(B) receptors in the spinal cord mediate both the antinociceptive and antiallodynic actions of intrathecal muscarine or neostigmine in normal rats and in a rat model of diabetic neuropathic pain. This study provides new functional evidence that activation of spinal GABA(B) receptors is one of the important mechanisms underlying the antinociceptive action of intrathecal cholinergic agents.
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PMID:Spinal GABAB receptors mediate antinociceptive actions of cholinergic agents in normal and diabetic rats. 1259 Nov 21

Serotonin type 2 (5-HT(2)) receptors reportedly inhibit neuropathic pain in the spinal cord, but little is known about how spinal 5-HT(2) receptors might act against such abnormal sensitivity. We examined whether the cholinergic and tachykinin systems were involved in the antiallodynic effect of intrathecally administered 5-HT(2) receptor agonists in rats with nerve injury. Allodynia was produced by tight ligation of the left L5 and L6 spinal nerves, and determined by applying von Frey hairs to the left hindpaw. Effects of intrathecal pretreatment with 5-HT(2) receptor antagonists (ketanserin and RS-102221), muscarinic receptor antagonists (atropine and scopolamine), a choline uptake blocker (hemicholium-3), and an NK(1) receptor antagonist (L-706336) were assessed in rats subsequently given a 100- micro g intrathecal dose of a 5-HT(2) receptor agonist either alpha-methyl-5-HT or iododimethoxy aminopropane (DOI). Antiallodynic effects of 5-HT(2) receptor agonists were attenuated by the 5-HT(2A) receptor antagonist ketanserin (30 micro g), but not by the 5-HT(2C) receptor antagonist RS-102221 (40 micro g). Muscarinic receptor antagonists (30 micro g each), the choline uptake blocker (10 micro g), and the NK(1) receptor antagonist (30 micro g) also inhibited the antiallodynic effects of 5-HT(2) receptor agonists. Antiallodynic effects of intrathecally administered 5-HT(2) receptor agonists may be mediated by spinal release of acetylcholine induced via 5-HT(2A) and NK(1) receptors.
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PMID:Interactions of 5-HT2 receptor agonists with acetylcholine in spinal analgesic mechanisms in rats with neuropathic pain. 1259 Nov 27

We examined the involvement of the spinal muscarinic receptors in the clonidine-induced antiallodynic effects. Mechanical sensitivity was assessed by stimulating the hind paw with von Frey filaments. In streptozotocin-treated (200 mg/kg, i.v.) diabetic mice, hypersensitivity to mechanical stimulation appeared 3 days after streptozotocin administration, and persisted for 11 days. This mechanical hypersensitivity (allodynia) was inhibited by the intrathecal (i.t.) injection of clonidine. The muscarinic receptor antagonist atropine (i.t.) and alpha2-adrenoreceptor antagonist yohimbine (i.t. or subcutaneous injection) abolished the antiallodynic effect of clonidine. The effect was mimicked by the muscarinic M1 receptor antagonist pirenzepine, but not by the muscarinic M2 receptor antagonist methoctoramine or the muscarinic M3 receptor antagonist 4-DAMP (4-diphenyl-acetoxy-N-methylpiperidine methiodide). In addition, the mechanical hypersensitivity in diabetic mice was reduced by the selective muscarinic M1 receptor agonist McN-A-343 (4-(m-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride) (i.t.). These results suggest that spinal muscarinic M1 receptors participate in the antiallodynic effect of clonidine in diabetic mice.
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PMID:Intrathecal clonidine inhibits mechanical allodynia via activation of the spinal muscarinic M1 receptor in streptozotocin-induced diabetic mice. 1555 39

Antidepressants are often used to treat neuropathic pain. In the present study, we determined the antiallodynic effects of selective monoamine reuptake inhibitors in the spinal cord in a rat model of neuropathic pain. Mechanical allodynia was produced by tight ligation of the left L5 and L6 spinal nerves and determined by applying von Frey filaments to the left hindpaw. A serotonin noradrenaline reuptake inhibitor, milnacipran, a selective serotonin reuptake inhibitor, paroxetine, or a selective noradrenaline reuptake inhibitor, maprotiline, was administered intrathecally via a chronically implanted catheter. Milnacipran produced dose-dependent antiallodynic effects at doses between 3 microg and 100 microg. The effect lasted for 7 h after injection of 100 microg (P < 0.05). The antiallodynic effect of 30 microg of milnacipran was attenuated by intrathecal coadministration of 30 microg of yohimbine, an alpha(2)-adrenoceptor antagonist, 30 microg of methysergide, a serotonin receptor antagonist, or 30 microg of atropine, a muscarinic receptor antagonist (P < 0.01, respectively). Intraperitoneal administration of milnacipran had no antiallodynic effects at doses of 3 to 30 mg/kg. Antiallodynic effects were not produced by intrathecal administration of paroxetine (10 to 100 microg) or maprotiline (10 to 100 microg). These findings suggest that simultaneous inhibition of serotonin and noradrenaline reuptake in the spinal cord is essential to mediate antiallodynic effects. Milnacipran might be effective for suppression of neuropathic pain.
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PMID:The monoamine-mediated antiallodynic effects of intrathecally administered milnacipran, a serotonin noradrenaline reuptake inhibitor, in a rat model of neuropathic pain. 1584 95

Intrathecal administration of serotonin type 2C (5-HT(2C)) receptor agonists produces an antiallodynic effect in a rat model of neuropathic pain. In the present study, we characterized this effect pharmacologically. Allodynia was produced by tight ligation of the fifth (L5) and sixth (L6) lumbar spinal nerves on the left side, and was measured by applying von Frey filaments to the left hindpaw. 6-chloro-2-(1-piperazinyl)-pyrazine (MK212; 100 microg) and 1-(m-chlorophenyl)-piperazine (mCPP; 300 microg) were used as 5-HT(2C) receptor agonists. Intrathecal administration of these agonists resulted in an antiallodynic effect. Intrathecal administration of atropine (30 mug), a muscarinic receptor antagonist, and yohimbine (30 microg), an alpha(2)-adrenoceptor antagonist, reversed the effects of 5-HT(2C) receptor agonists. Intrathecal pretreatment with 6-hydroxydopamine, an adrenergic neurotoxin, inhibited the antiallodynic effect of MK212. These results suggest that spinal noradrenergic mechanisms are involved in the antiallodynic effects of intrathecally administered 5-HT(2C) receptor agonists. Previously, we demonstrated that intrathecal administration of 5-HT(2A) receptor agonists also produced antiallodynic effects, and the effects were not reversed by yohimbine. Taken together, these findings suggest that 5-HT(2A) and 5-HT(2C) receptors in the dorsal horn of the spinal cord might be involved in alleviating neuropathic pain by different mechanisms.
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PMID:Possible involvement of spinal noradrenergic mechanisms in the antiallodynic effect of intrathecally administered 5-HT2C receptor agonists in the rats with peripheral nerve injury. 1745 74

Spinal cord stimulation (SCS) has proven to be a valuable treatment in neuropathic pain. Our previous animal experiments performed on rat models of SCS and ensuing clinical trials have demonstrated that intrathecal (i.t.) administration of subeffective doses of certain drugs may enhance the pain relieving effect of SCS in cases with unsatisfactory SCS outcome. Recently, an augmented release of spinal acetylcholine acting on muscarinic receptors has been shown to be one of the mechanisms involved in SCS. The present study was performed to examine whether cold hypersensitivity and heat hyperalgesia in rats with partial sciatic nerve injuries can be attenuated by SCS in the same way as tactile hypersensitivity and to explore a possibly synergistic effect of SCS and a muscarinic receptor agonist, oxotremorine. Rats with signs of neuropathy were subjected to SCS applied in awake, freely moving condition. Oxotremorine was administered intrathecally. Tactile, cold and heat sensitivities were assessed by using von Frey filaments, cold spray and focused radiant heat, respectively. Oxotremorine i.t. dose-dependently suppressed the tactile hypersensitivity. SCS markedly increased withdrawal thresholds (WTs), withdrawal latencies and cold scores. When combining SCS with a subeffective dose of oxotremorine i.t., the suppressive effect of SCS on the pain-related symptoms was dramatically enhanced in rats failing to obtain a satisfactory effect with SCS alone. In conclusion, the combination of SCS and a drug with selective muscarinic receptor agonistic properties could be an optional therapy, when SCS per se has proven inefficient.
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PMID:Muscarinic receptor activation potentiates the effect of spinal cord stimulation on pain-related behavior in rats with mononeuropathy. 1834 81

1. Cholinergic agonists and acetylcholinesterase inhibitors, such as neostigmine, produce a muscarinic receptor-mediated antinociception in several animal species that depends on activation of spinal cholinergic neurons. However, neostigmine causes antinociception in sheep only in the early, and not late, postoperative period. 2. In the present study, a model of postoperative pain was used to determine the antinociceptive effects of bethanechol (a muscarinic agonist) and neostigmine administered intrathecally 2, 24 or 48 h after a plantar incision in a rat hind paw. Changes in the threshold to punctate mechanical stimuli were evaluated using an automated electronic von Frey apparatus. 3. Mechanical hyperalgesia was obtained following plantar incision, the effect being stronger during the immediate (2 h) than the late post-surgical period. Bethanechol (15-90 microg/5 microL) or neostigmine (1-3 microg/5 microL) reduced incision-induced mechanical hyperalgesia, the effects of both drugs being more intense during the immediate (2 h) than the late post-surgical period. 4. The ED(50) for bethanechol injected at 2, 24 and 48 h was 5.6, 51.9 and 82.5 microg/5 microL, respectively. The corresponding ED(50) for neostigmine was 1.62, 3.02 and 3.8 microg/5 microL, respectively. 5. The decline in the antinociceptive potency of neostigmine with postoperative time is interpreted as resulting from a reduction in pain-induced activation of acetylcholine-releasing descending pathways. However, the similar behaviour of bethanechol in the same model points to an additional mechanism involving intrinsic changes in spinal muscarinic receptors.
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PMID:Postoperative analgesia induced by intrathecal neostigmine or bethanechol in rats. 1907 63