Potent muscarinic analgesics derived from epibatidine: Role of the M4 receptor subtype

Ellis, James L.; Harman, Denham; González, J.; Sepra, M.L.; Liu, R.; Shen, T. Y.; Wypij, Donna M.; Zuo, Fanglei

doi:10.1016/s0024-3205(99)90468-x

Cited by 22 publications

(51 citation statements)

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“…Due to lack of specific radioligands for muscarinic receptors other than the M2 subtype, we were unable to determine potential changes in other muscarinic subtypes in diabetes. It has been reported that muscarinic toxin-3 is specific for muscarinic M4 subtype (Ellis et al, 1999). Thus, this toxin may be useful to determine the potential change of the M4 subtype in the spinal cord in diabetes.…”

Section: Discussionmentioning

confidence: 99%

Up-Regulation of Spinal Muscarinic Receptors and Increased Antinociceptive Effect of Intrathecal Muscarine in Diabetic Rats

Chen

Pan²

2003

J Pharmacol Exp Ther

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Spinally administered muscarinic receptor agonists or acetylcholinesterase inhibitors produce effective pain relief. Intrathecal injection of a small dose of neostigmine produces a profound antiallodynic effect in rats with diabetic neuropathy. However, the mechanisms of increased antinociceptive effect of cholinergic agents on diabetic neuropathic pain are not clear. In the present study, we tested the hypothesis that spinal muscarinic receptors are up-regulated in diabetes. The withdrawal threshold of the hindpaw in response to noxious heat and pressure stimuli was determined in streptozotocin-induced diabetic and age-matched normal rats. 3 H]AF-DX 384 membrane binding was performed to determine the number and affinity of spinal cord M2 muscarinic receptors in normal and diabetic rats. We found that the antinociceptive effect of intrathecal 2 to 12 g muscarine in diabetic animals was potentiated significantly compared with that in normal animals. The maximal muscarine-stimulated [35 S]GTP␥S binding was 112.5 Ϯ 8.3% in normal rats and 168.8 Ϯ 12.1% (P Ͻ 0.05) in diabetic rats. Although the K D value (2.9 nM) was similar in both groups, the B max of [ 3 H]AF-DX 384 membrane binding was significantly higher in diabetic than in normal rats (255.2 Ϯ 5.9 versus 165.9 Ϯ 3.5 fmol/mg protein, P Ͻ 0.05). Collectively, these data strongly suggest that the muscarinic receptor is up-regulated in the dorsal spinal cord in diabetic rats. This finding probably accounts for the increased efficacy of the antinociceptive effect of intrathecal muscarinic agonists in diabetic neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

Up-Regulation of Spinal Muscarinic Receptors and Increased Antinociceptive Effect of Intrathecal Muscarine in Diabetic Rats

Chen

Pan²

2003

J Pharmacol Exp Ther

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“…Also, because intrathecal injection of the selective M 4 receptor antagonist muscarinic toxin-3 reduces the antinociceptive effect of mAChR agonists in mice (Ellis et al, 1999), functional M 4 mAChRs are likely to exist in the mouse spinal cord dorsal horn. Additionally, the analgesic action of intrathecal muscarinic agonists is largely attenuated (by ϳ60 -90%), but not abolished, in M 2 single-KO mice (Duttaroy et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…The M 1 , M 3 , and M 5 receptor subtypes couple preferentially to the G q/11 protein, whereas the M 2 and M 4 receptors are preferentially coupled to G i/o proteins (Caulfield, 1993;Felder, 1995). In rodents, both the M 2 and M 4 subtypes that are coupled to the pertussis toxinsensitive G i/o proteins have been implicated in the inhibitory effect of mAChR agonists on nociception and spinal dorsal horn neurons (Ellis et al, 1999;Gomeza et al, 1999a;Duttaroy et al, 2002;Chen and Pan, 2004). Recent studies in mutant mouse lines deficient in M 2 and M 4 mAChRs [knockout (KO) mice] indicate that the spinal analgesic effect produced by mAChR agonists is mediated by M 2 and M 4 subtypes (Gomeza et al, 1999a;Duttaroy et al, 2002).…”

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confidence: 99%

Functional Activity of the M₂ and M₄ Receptor Subtypes in the Spinal Cord Studied with Muscarinic Acetylcholine Receptor Knockout Mice

Chen¹,

Wess²,

Pan³

2005

J Pharmacol Exp Ther

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Stimulation of spinal muscarinic acetylcholine receptors (mAChRs) produces potent analgesia. Both M 2 and M 4 mAChRs are coupled to similar G proteins (G i/o family) and play a critical role in the analgesic action of mAChR agonists. To determine the relative contribution of M 2 and M 4 The cholinergic system and muscarinic acetylcholine receptors (mAChRs) in the dorsal horn of the spinal cord are important for regulation of different physiological functions including nociception. In this regard, intrathecal administration of muscarinic receptor agonists or acetylcholinesterase inhibitors produces potent analgesia in both animals and humans (Iwamoto and Marion, 1993; Yaksh, 1994, 1997;Hood et al., 1997). The analgesic effect produced by muscarinic receptor agonists or acetylcholinesterase inhibitors is blocked by the mAChR antagonist atropine (Naguib and Yaksh, 1994). Furthermore, spinal acetylcholine and mAChRs are involved in the analgesic action produced by morphine and ␣ 2 -adrenergic receptor agonists (Pan et al., 1999;Chen and Pan, 2001). It has been shown that neurons and nerve terminals expressing choline acetyltransferase and acetylcholinesterase (enzymes for acetylcholine synthesis and degradation) are located in the spinal dorsal horn (Ribeiro-da-Silva and Cuello, 1990;Wetts and Vaughn, 1994). Autoradiographic studies have demonstrated that the highest density of mAChRs in the spinal cord is distributed in the superficial laminae in both rats and humans (Yamamura et al., 1983;Villiger and Faull, 1985;Maher et al., 2001).Molecular cloning studies have revealed the existence of five molecularly distinct mAChR subtypes referred to as M 1 to M 5 (Wess, 1996;Caulfield and Birdsall, 1998). The M 1 to M 5 mAChRs are prototypical members of the superfamily of G protein-coupled receptors. The M 1 , M 3 , and M 5 receptor subtypes couple preferentially to the G q/11 protein, whereas the M 2 and M 4 receptors are preferentially coupled to G i/o proteins (Caulfield, 1993;Felder, 1995). In rodents, both the M 2 and M 4 subtypes that are coupled to the pertussis toxinsensitive G i/o proteins have been implicated in the inhibitory

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“…In this regard, blockade of mAChRs with atropine in the spinal cord causes a large decrease in the nociceptive threshold in rats (Zhuo and Gebhart, 1991). Intrathecal administration of mAChR agonists or acetylcholinesterase inhibitors produces a potent analgesic effect in rats, mice, and humans (Naguib and Yaksh, 1994;Hood et al, 1997;Ellis et al, 1999;Duttaroy et al, 2002;Chen and Pan, 2003c), and this analgesic effect is blocked by atropine (Naguib and Yaksh, 1994). The mAChRs also mediate some of the antinociceptive effects of opioids (Chen and Pan, 2001) and can enhance the analgesic effect of systemic opioids in humans (Hood et al, 1997).…”

Section: Antinociceptive Effect Of Machr Agonistsmentioning

confidence: 99%

Modulation of pain transmission by G-protein-coupled receptors

Pan

Zhou

et al. 2008

Pharmacology & Therapeutics

167

116

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The heterotrimeric G protein-coupled receptors (GPCRs) represent the largest and most diverse family of cell surface receptors and proteins. GPCRs are widely distributed in the peripheral and central nervous systems and are one of the most important therapeutic targets in pain medicine. GPCRs are present on the plasma membrane of neurons and their terminals along the nociceptive pathways and are closely associated with the modulation of pain transmission. GPCRs that can produce analgesia upon activation include opioid, cannabinoid, α 2 -adrenergic, muscarinic acetylcholine, γ-aminobutyric acid B (GABA B ), group II and III metabotropic glutamate, and somatostatin receptors. Recent studies have led to a better understanding of the role of these GPCRs in the regulation of pain transmission. Here, we review the current knowledge about the cellular and molecular mechanisms that underlie the analgesic actions of GPCR agonists, with a focus on their effects on ion channels expressed on nociceptive sensory neurons and on synaptic transmission at the spinal cord level.

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Potent muscarinic analgesics derived from epibatidine: Role of the M4 receptor subtype

Cited by 22 publications

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Up-Regulation of Spinal Muscarinic Receptors and Increased Antinociceptive Effect of Intrathecal Muscarine in Diabetic Rats

Up-Regulation of Spinal Muscarinic Receptors and Increased Antinociceptive Effect of Intrathecal Muscarine in Diabetic Rats

Functional Activity of the M₂ and M₄ Receptor Subtypes in the Spinal Cord Studied with Muscarinic Acetylcholine Receptor Knockout Mice

Modulation of pain transmission by G-protein-coupled receptors

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Potent muscarinic analgesics derived from epibatidine: Role of the M4 receptor subtype

Cited by 22 publications

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Up-Regulation of Spinal Muscarinic Receptors and Increased Antinociceptive Effect of Intrathecal Muscarine in Diabetic Rats

Up-Regulation of Spinal Muscarinic Receptors and Increased Antinociceptive Effect of Intrathecal Muscarine in Diabetic Rats

Functional Activity of the M2 and M4 Receptor Subtypes in the Spinal Cord Studied with Muscarinic Acetylcholine Receptor Knockout Mice

Modulation of pain transmission by G-protein-coupled receptors

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Functional Activity of the M₂ and M₄ Receptor Subtypes in the Spinal Cord Studied with Muscarinic Acetylcholine Receptor Knockout Mice