Re: 2010년 5월 30일. 침의 진통기전에 대한 기념비적 연구 발표(fulltext)

[문형철]

2010년 5월 30일.. 침의 효과에 대한 "기념비적인 기전"을 밝힌 논문

Nature science에..

panic bird..

Adenosine in the spinal cord and periphery..pdf

Prog Neurobiol. 2003 Apr;69(5):313-40.

Adenosine in the spinal cord and periphery: release and regulation of pain.

Sawynok J, Liu XJ.

Department of Pharmacology, Dalhousie University, Halifax, NS Canada B3H 1X5. jana.saeynok@dal.ca

Abstract

In the central nervous system (CNS), adenosine is an important neuromodulator and regulates neuronal and non-neuronal cellular function (e.g. microglia) by actions on extracellular adenosine A(1), A(2A), A(2B) and A(3) receptors. Extracellular levels of adenosine are regulated by synthesis, metabolism, release and uptake of adenosine. Adenosine also regulates pain transmission in the spinal cord and in the periphery, and a number of agents can alter the extracellular availability of adenosine and subsequently modulate pain transmission, particularly by activation of adenosine A(1) receptors. The use of capsaicin (which activates receptors selectively expressed on C-fibre afferent neurons and produces neurotoxic actions in certain paradigms) allows for an interpretation of C-fibre involvement in such processes. In the spinal cord, adenosine availability/release is enhanced by depolarization (K(+), capsaicin, substance P, N-methyl-D-aspartate (NMDA)), by inhibition of metabolism or uptake (inhibitors of adenosine kinase (AK), adenosine deaminase (AD), equilibrative transporters), and by receptor-operated mechanisms (opioids, 5-hydroxytryptamine (5-HT), noradrenaline (NA)). Some of these agents release adenosine via an equilibrative transporter indicating production of adenosine inside the cell (K(+), morphine), while others release nucleotide which is converted extracellularly to adenosine by ecto-5'-nucleotidase (capsaicin, 5-HT). Release can be capsaicin-sensitive, Ca(2+)-dependent and involve G-proteins, and this suggests that within C-fibres, Ca(2+)-dependent intracellular processes regulate production and release of adenosine. In the periphery, adenosine is released from both neuronal and non-neuronal sources. Neuronal release from capsaicin-sensitive afferents is induced by glutamate and by neurogenic inflammation (capsaicin, low concentration of formalin), while that from sympathetic postganglionic neurons (probably as adenosine 5'-triphosphate (ATP) with NA) occurs following more generalized inflammation. Such release is modified differentially by inhibitors of AK and AD. Following nerve injury, there is an alteration in capsaicin-sensitive adenosine release, as spinal release now is less responsive to opioids, while peripheral release is less responsive to inhibitors of metabolism. Following inflammation, adenosine is released from a variety of cell types in addition to neurons (e.g. endothelial cells, neutrophils, mast cells, fibroblasts). ATP is released both spinally and peripherally following inflammation or injury, and may be converted to adenosine by ecto-5'-nucleotidase contributing an additional source of adenosine. Release of adenosine from both spinal and peripheral compartments has inhibitory effects on pain transmission, as methylxanthine adenosine receptor antagonists reduce analgesia produced by agents which augment extracellular levels of adenosine spinally (morphine, 5-HT, substance P, AK inhibitors) and peripherally (AK inhibitors, AD inhibitors). Increases in extracellular adenosine availability also may contribute to antiinflammatory effects of certain agents (methotrexate, sulfasalazine, salicylates, AK inhibitors), and this could have secondary effects on pain signalling in chronic inflammation. The purpose of the present review is to consider: (a). the factors that regulate the extracellular availability of adenosine in the spinal cord and at peripheral sites; and (b). the extent to which this adenosine affects pain signalling in these two distinct compartments.

Increased nociceptive response in mice lacking the adenosine A1 receptor
Wei-Ping Wua, Jing-Xia Haoa, Linda Halldnerb, Cecilia Lo¨vdahlb, Gary E. DeLanderb,c, Zsuzsanna Wiesenfeld-Hallina, Bertil B. Fredholmb, Xiao-Jun Xua,*
aDepartment of Neurotec, Division of Clinical Neurophysiology, Karolinska Institutet, Karolinska University Hospital-Huddinge, S-141 86 Stockholm, Sweden
bDepartment of Physiology and Pharmacology, Section of Molecular Neuropharmacology, Karolinska Institutet, S-141 86 Stockholm, Sweden
cDepartment of Pharmacology, College of Pharmacy, Oregon State University, Corvallis, OR 97311-3507, USA
Received 27 August 2004; received in revised form 5 November 2004; accepted 22 November 2004

Abstract
The role of the adenosine A1 receptor in nociception was assessed using mice lacking the A1 receptor (A1RK/K) and in rats. Under normal conditions, the A1RK/K mice exhibited moderate heat hyperalgesia in comparison to the wild-type mice (A1RC/C). The mechanical and cold sensitivity were unchanged. The antinociceptive effect of morphine given intrathecally (i.t.), but not systemically, was reduced in A1RK/K mice and this reduction in the spinal effect of morphine was not associated with a decrease in binding of the m-opioid ligand DAMGO in the spinal cord. A1RK/K mice also exhibited hypersensitivity to heat, but not mechanical stimuli, after localized inflammation induced by carrageenan. In mice with photochemically induced partial sciatic nerve injury, the neuropathic pain-like behavioral response to heat or cold stimulation were significantly increased in the A1RK/Kmice. Peripheral nerve injury did not change the level of adenosine A1 receptor in the dorsal spinal cord in rats and i.t. administration of R-PIA effectively alleviated pain-like behaviors after partial nerve injury in rats and in C57/BL/6 mice. Taken together, these data suggest that the adenosine A1 receptor plays a physiological role
in inhibiting nociceptive input at the spinal level in mice. The C-fiber input mediating noxious heat is inhibited more than other inputs. A1 receptors also contribute to the antinociceptive effect of spinal morphine. Selective A1 receptor agonists may be tested clinically as analgesics, particularly under conditions of neuropathic pain.

1. Introduction
Adenosine is a ubiquitous endogenous neurotransmitter/modulator (Dunwiddie and Masino, 2001). It acts on specific membrane-bound G-protein coupled receptors(Klinger et al., 2002; Ribeiro et al., 2003) and four subtypes of adenosine receptors (AR), A1R, A2AR, A2BR, and A3R, have been cloned and pharmacologically characterized (Fredholm et al., 2001).
A1R and A2AR binding sites have been found in the dorsal horn of the spinal cord, particularly in the substantia gelatinosa (Choca et al., 1987, 1988). The A1R is mostly located on intrinsic dorsal horn neurons, but there are also some A1R on dorsal root ganglion (DRG) cells (Schulte et al., 2003). Although some A2AR can be detected in spinal cord, the mRNA for A2AR is not found there, but in the DRG(Kaelin-Lang et al., 1998, 1999). Activation of A1R primarily produces inhibition of neuronal activity in the spinal cord and DRG (Deuchars et al., 2001; Dolphin et al.,1986; Li and Perl, 1994; Patel et al., 2001; Reeve and
Dickenson, 1995; Salter et al., 1993).

Systemic or spinal administration of adenosine analogs produces antinociception in a wide range of tests (Karlsten
et al., 1990; Keil and DeLander, 1992; Post, 1984; see Sawynok and Liu, 2003; Sawynok et al., 1986 for review). Adenosine analogs also produce motor effect when given spinally, effects that are nonetheless distinguishable from antinociception (Karlsten et al., 1990; Sawynok and Poon, 1999). It is believed that the A1R is responsible for the antinociceptive effect of adenosine analogues (Lee and Yaksh, 1996; Nakamura et al., 1997; Poon and Sawynok, 1998; but see DeLander and Keil, 1994). Adenosine analogues are effective in treating neuropathic pain in animal models (Cui et al., 1997; Gomes et al., 1999; Lavand’homme and Eisenach, 1999; Lee and Yaksh, 1996; Von Heijne et al.,2000) and in clinical studies (Belfrage et al., 1995, 1999; Karlsten and Gordh, 1995). Spinal release of adenosine has also been implicated in spinal and supraspinal morphine antinociception (Delander and Hopkins, 1986; Sweeney et al., 1987, 1989; see Sawynok and Liu, 2003 for review).

Although extensive data have been gathered concerning the effect of exogenous adenosine on nociception, relatively
little is known about the physiological significance of adenosine and its respective receptors. Mice with a targeted
deletion of receptor genes provided a new avenue for analyzing the physiology of adenosine receptors. Mice lacking A2AR were shown to be hypoalgesic, probably reflecting a peripheral pro-nociceptive function (Ledent et al., 1997). We showed that mice lacking A1Rs exhibited moderate hyperalgesia to heat stimulation (Johansson et al., 2001). The present study aimed to extend our previous studies by examining the responses of A1R knock-out (A1RK/K) mice to inflammation or partial sciatic nerve injury. We also assessed the contribution of A1R in spinal vs. systemic morphine antinociception. The effect of intrathecal (i.t.) R-phenyl-isopropyl adenosine (R-PIA), a somewhat A1R selective agonist, on neuropathic pain-like behaviors in mice and rats with partial nerve injury was also examined as was the density of A1R binding after nerve injury in rats.

사전에서 발췌한 자료

In humans, there are four adenosine receptors. Each is encoded by a separate gene and has different functions, although with some overlapping.^[3] For instance, both A₁ receptors and A_2A play roles in the heart, regulating myocardial oxygen consumption and coronary blood flow, while the A_2A receptor also has broader antiinflammatory effects throughout the body.^[4] These two receptors also have important roles in the brain,^[5] regulating the release of other neurotransmitters such as dopamine and glutamate,^[6][7][8] while the A_2B and A₃ receptors are located mainly peripherally and are involved in processes such as inflammation and immune responses.

Most older compounds acting on adenosine receptors are n[안내]태그제한으로등록되지않습니다-xx[안내]태그제한으로등록되지않습니다-xx[안내]태그제한으로등록되지않습니다-xx[안내]태그제한으로등록되지않습니다-xx[안내]태그제한으로등록되지않습니다-xx[안내]태그제한으로등록되지않습니다-xx[안내]태그제한으로등록되지않습니다-xx[안내]태그제한으로등록되지않습니다-xxonselective, with the endogenous agonist adenosine being used in hospitals as treatment for severe tachycardia (rapid heart beat),^[9] and acting directly to slow the heart through action on all four adenosine receptors in heart tissue,^[10] as well as producing a sedative effect through action on A₁ and A_2A receptors in the brain. Xanthine derivatives such as caffeine and theophylline act as non-selective antagonists at A₁ and A_2A receptors in both heart and brain and so have the opposite effect to adenosine, producing a stimulant effect and rapid heart rate.^[11] These compounds also act as phosphodiesterase inhibitors, which produces additional antiinflammatory effects, and makes them medically useful for the treatment of conditions such as asthma, but less suitable for use in scientific research.^[12]

Newer adenosine receptor agonists and antagonists are much more potent and subtype-selective, and have allowed extensive research into the effects of blocking or stimulating the individual adenosine receptor subtypes, which is now resulting in a new generation of more selective drugs with many potential medical uses. Some of these compounds are still derived from adenosine or from the xanthine family, but researchers in this area have also discovered many selective adenosine receptor ligands that are entirely structurally distinct, giving a wide range of possible directions for future research

Adenosine A₁ receptor

The adenosine A₁ receptor^[1] is one member of the adenosine receptor group of G protein-coupled receptors with adenosine as endogenous ligand. A₁ receptors are implicated in sleep promotion by inhibiting wake promoting cholinergic neurons in the basal forebrain.^[2] A₁ receptors are also present in smooth muscle throughout the vascular system.^[3]

The adenosine A₁ receptor has been found to be ubiquitous throughout the entire body.

This receptor has an inhibitory function on most of the tissues in which it is expressed. In the brain, it slows metabolic activity by a combination of actions. Presynaptically, it reduces synaptic vesicle release while post synaptically it has been found to stabilize the magnesium on the NMDA receptor.

Signaling

Activation of the adenosine A₁ receptor by an agonist causes binding of G_i1/2/3 or G_o protein. Binding of G_i1/2/3 causes an inhibition of adenylate cyclase and therefore a decrease in the cAMP concentration. An increase of the inositol triphosphate/diacylglycerol concentration is caused by an activation of phospholipase C while the elevated levels of arachidonic acid are mediated by phospholipase 2A Several types of potassium channels are activated but N-, P- and Q-type calcium channels are inhibited.^[4]

Mechanism

This receptor has an inhibitory function on most of the tissues in which it rests. In the brain, it slows metabolic activity by a combination of actions. Presynaptically, it reduces synaptic vesicle release.

Agonists

• 2-chloro-N(6)-cyclopentyladenosine (CCPA).
• N6-Cyclopentyladenosine
• N(6)-cyclohexyladenosine

Antagonists

Non-selective

• Caffeine
• Theophylline

Selective

• 8-Cyclopentyl-1,3-dimethylxanthine (CPX / 8-cyclopentyltheophylline)
• 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX)
• 8-Phenyl-1,3-dipropylxanthine
• Bamifylline
• BG-9719^[5]
• BG-9928^[6]
• FK-453
• FK-838
• Rolofylline (KW-3902)^[7][8]
• N-0861

in heart

The A₁, together with A_2A receptors, of endogenous adenosine are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow. Stimulation of the A₁ receptor has a myocardial depressant effect by decreasing the conduction of electrical impulses and suppressing pacemaker cell function, resulting in a decrease in heart rate. This makes adenosine a useful medication for treating and diagnosing tachyarrhythmias, or excessively fast heart rates. This effect on the A₁ receptor also explains why there is a brief moment of cardiac standstill when adenosine is administered as a rapid IV push during cardiac resuscitation. The rapid infusion causes a momentary myocardial stunning effect.

In normal physiological states, this serves as protective mechanisms. However, in altered cardiac function, such as hypoperfusion caused by hypotension, heart attack or cardiac arrest caused by nonperfusing bradycardias, adenosine has a negative effect on physiological functioning by preventing necessary compensatory increases in heart rate and blood pressure that attempt to maintain cerebral perfusion.

The antinociceptive effects of the systemic adenosine A1 receptor agonist CPA in the absence and in the presence of spinal cord sensitization

 

M. Mar Curros-Criado and Juan F. Herrero ^,

Departamento de Fisiología, Facultad de Medicina, Universidad de Alcalá, Madrid, Spain

Received 21 July 2005; 

accepted 24 November 2005. 

Available online 5 January 2006.

Abstract

Adenosine A1 receptor agonists are effective antinociceptive agents in neuropathic and inflammatory pain, though they appear to be weak analgesics in acute nociception. Important discrepancies are observed on the effectiveness and potency of adenosine analogues when comparing different studies, probably due to the use of different ligands, models of antinociception, routes of administration and types of sensitization.

We studied the systemic antinociceptive effects of the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) in spinal cord neuronal responses from adult male rats in acute nociception and in sensitization due to arthritis and neuropathy. The experiments showed that CPA was effective in the three experimental conditions, with a similar potency in reducing responses to noxious mechanical stimulation (ID50s: 20 ± 1.2 μg/kg in acute nociception, 18 ± 1.1 μg/kg in arthritis, 17.4 ± 2 μg/kg in neuropathy). The phenomenon of wind-up was also dose-dependently reduced by CPA in the three experimental situations although the main action was seen in arthritis. Depression of blood pressure by CPA was not dose-dependent. We conclude that systemic CPA is a potent and effective analgesic in sensitization due to arthritis and neuropathy but also in acute nociception. The effect is independent of the cardiovascular activity and is centrally mediated since wind-up was inhibited.

abstract

Acupuncture is an invasive procedure commonly used to relieve pain. Acupuncture is practiced worldwide, despite difficulties in reconciling its principles with evidence-based medicine. We found that adenosine, a neuromodulator with anti-nociceptive properties, was released during acupuncture in mice and that its anti-nociceptive actions required adenosine A1 receptor expression‎. Direct injection of an adenosine A1 receptor agonist replicated the analgesic effect of acupuncture. Inhibition of enzymes involved in adenosine degradation potentiated the acupuncture-elicited increase in adenosine, as well as its anti-nociceptive effect. These observations indicate that adenosine mediates the effects of acupuncture and that interfering with adenosine metabolism may prolong the clinical benefit of acupuncture.

Adenosine A1 receptors mediate local anti-nociceptive effec.pdf

The antinociceptive effect of systemic gabapentin is relate.pdf

Increased nociceptive response in mice lacking the adenosin.pdf

[김태윤]

침의 작동원리가 서양의학적 근거에 의해서 규명된것도 사실이지만, 반대로 그들의 논리에 의해서 입증된만큼 양방의사들의 침사용에 대한 근거를 제시한 것일 수도 있다고 생각합니다
그들의 입장에서 보면, "여태까지는 전통의학적인 근거에 의해서 침을 운용하여야 하므로 침구학을 이해하지 못하는 양방의사들이 침을 사용하는 것에 대해서 한의사들이 반대해왔지만, 이 논문을 통해서 침을 사용하면 adenosine에 의한 pain control을 할 수 있는 것이 밝혀진만큼 이것이 양방치료의 일부분이되어야 한다."라고 주장할 수도 있을 것같네요

[김태윤]

이에 더해 A라는 혈자리와 B라는 혈자리가 있다고 할 때 A만을 자침했을 때는 adenosine이 나오지 않고, A와 B를 동시에 자침했을 때에만 adenosine에 의한 pain control이 있기 때문에, 정확한 선혈을 하지 않는다면 진통효과를 재현할 수 없다...이런 논리에서 서술한 논문이 아니기에 더더욱 그런생각이 강하게 듭니다.

[베이커스]

그렇게 볼 수도 있겠네요.. 뒤늦게 한의심터에서 보고 왔습니다.