The role of adenosine and its receptor subtypes in nociception and neuropathic pain
Author: Wu, Weiping
Date: 2005-06-17
Location: R 64, Karolinska Universitetssjukhuset, Huddinge
Time: 9.00
Department: Institutionen för laboratoriemedicin / Department of Laboratory Medicine
Abstract
As neurotransmitter/modulator, adenosine plays an important role in nociceptive processing. Adenosine receptors are G-protein coupled and four receptor subtypes, A1, A2A, A2B and A3 have been identified. It is well established that adenosine and its receptor agonists produce primarily antinociceptive effect in animals and humans. The physiological significance of endogenous adenosine and its receptors in pain modulation, including neuropathic pain (pain after injury or diseases to the nervous system) is, however, less clear.
In the first part of this thesis, we have used mice with targeted deletion of adenosine A1 and A3 receptors to explore their individual roles in nociception. In the second part of the thesis, we studied the effect of caffeine, a non-selective antagonist of adenosine receptors, in a rat model of neuropathic pain and explored potential genetic factors in the antinociceptive effect of the adenosine analogue R (-N 6 -2-Phenylisopropyl) adenosine (R-PIA) using inbred mice.
To aid these studies, we developed anew method for chronic intrathecal (i.t.) catheterization in mice. A1, but not A3, knock out mice exhibited heat hyperalgesia under normal condition and after carrageenan-induced inflammation, suggesting that the A1 receptor is physiologically active in inhibiting nociceptive input. A1 receptor, on the other hand, does not seem to play a role in localized inflammatory reaction to carrageenan. In contrast, canageenan-induced inflammation was reduced in the periphery in the A3 knock-out mice, which was associated with reduced inflammatory hyperalgesia. This suggests that adenosine A3 receptors play a pro-inflammatory role in peripheral tissues. The antinociceptive effect of i.t. R-PIA was abolished in A1, but not A3, knock-out mice. Further, the antinociceptive effect of i.t., but not systemic, morphine was also reduced in A, knockout mice.
These results suggest that the spinal A1 receptor is critical for adenosine analogue-mediated antinociception and the A, receptor is also involved in the spinal effect of morphine. Finally, mice lacking the A1 receptor had increased neuropathic pain-like behaviours after partial sciatic nerve injury and i.t. R-PIA was antinociceptive in the same model in rats and mice. These results indicate that the A1 receptor also plays inhibitory role after peripheral nerve injury and activation of this receptor may produce analgesic effect in neuropathic pain.
Chronic oral caffeine at high dose did not influence the development of neuropathic pain-like behaviours over 2 weeks in nerve injured rats, suggesting that the potential hyperalgesic effect of caffeine through blockade of the A1 receptor may have been masked by its antinociceptive effect, possibly mediated by a simultaneous blockade of the A2A receptor. The finding that high doses of caffeine intake did not affect the development of neuropathic pain may be of practical importance, considering the likelihood that many pain patients may consume large quantity of caffeine.
It is well known that there are genetic factors underlying individual sensitivity to pain and analgesics. We showed that the antinociceptive effect of i.t. R-PIA is significantly different among four inbred strains of mice, suggesting that there are genetic factors underlying variable response to adenosine receptor agonists in mice.
In the first part of this thesis, we have used mice with targeted deletion of adenosine A1 and A3 receptors to explore their individual roles in nociception. In the second part of the thesis, we studied the effect of caffeine, a non-selective antagonist of adenosine receptors, in a rat model of neuropathic pain and explored potential genetic factors in the antinociceptive effect of the adenosine analogue R (-N 6 -2-Phenylisopropyl) adenosine (R-PIA) using inbred mice.
To aid these studies, we developed anew method for chronic intrathecal (i.t.) catheterization in mice. A1, but not A3, knock out mice exhibited heat hyperalgesia under normal condition and after carrageenan-induced inflammation, suggesting that the A1 receptor is physiologically active in inhibiting nociceptive input. A1 receptor, on the other hand, does not seem to play a role in localized inflammatory reaction to carrageenan. In contrast, canageenan-induced inflammation was reduced in the periphery in the A3 knock-out mice, which was associated with reduced inflammatory hyperalgesia. This suggests that adenosine A3 receptors play a pro-inflammatory role in peripheral tissues. The antinociceptive effect of i.t. R-PIA was abolished in A1, but not A3, knock-out mice. Further, the antinociceptive effect of i.t., but not systemic, morphine was also reduced in A, knockout mice.
These results suggest that the spinal A1 receptor is critical for adenosine analogue-mediated antinociception and the A, receptor is also involved in the spinal effect of morphine. Finally, mice lacking the A1 receptor had increased neuropathic pain-like behaviours after partial sciatic nerve injury and i.t. R-PIA was antinociceptive in the same model in rats and mice. These results indicate that the A1 receptor also plays inhibitory role after peripheral nerve injury and activation of this receptor may produce analgesic effect in neuropathic pain.
Chronic oral caffeine at high dose did not influence the development of neuropathic pain-like behaviours over 2 weeks in nerve injured rats, suggesting that the potential hyperalgesic effect of caffeine through blockade of the A1 receptor may have been masked by its antinociceptive effect, possibly mediated by a simultaneous blockade of the A2A receptor. The finding that high doses of caffeine intake did not affect the development of neuropathic pain may be of practical importance, considering the likelihood that many pain patients may consume large quantity of caffeine.
It is well known that there are genetic factors underlying individual sensitivity to pain and analgesics. We showed that the antinociceptive effect of i.t. R-PIA is significantly different among four inbred strains of mice, suggesting that there are genetic factors underlying variable response to adenosine receptor agonists in mice.
List of papers:
I. Wu WP, Xu XJ, Hao JX (2004). Chronic lumbar catheterization of the spinal subarachnoid space in mice. J Neurosci Methods. 133(1-2): 65-9.
Pubmed
II. Wu WP, Hao JX, Halldner-Henriksson L, Xu XJ, Jacobson MA, Wiesenfeld-Hallin Z, Fredholm BB (2002). Decreased inflammatory pain due to reduced carrageenan-induced inflammation in mice lacking adenosine A3 receptors. Neuroscience. 114(3): 523-7.
Pubmed
III. Wu WP, Hao JX, Halldner L, Lovdahl C, DeLander GE, Wiesenfeld-Hallin Z, Fredholm BB, Xu XJ (2005). Increased nociceptive response in mice lacking the adenosine A1 receptor. Pain. 113(3): 395-404.
Pubmed
IV. Wu WP, Hao JX, Fredholm BB, Wiesenfeld-Hallin Z, Xu XJ (2005). Effect of acute and chronic administration of caffeine on pain-like behaviors in rats with partial sciatic nerve injury. [Manuscript]
V. Wu WP, Wiesenfeld-Hallin Z, Xu XJ (2005). Strain differences in the antinociceptive effect of intrathecal R-phenylisopropyl-adenosine (R-PIA): comparison with morphine. [Manuscript]
I. Wu WP, Xu XJ, Hao JX (2004). Chronic lumbar catheterization of the spinal subarachnoid space in mice. J Neurosci Methods. 133(1-2): 65-9.
Pubmed
II. Wu WP, Hao JX, Halldner-Henriksson L, Xu XJ, Jacobson MA, Wiesenfeld-Hallin Z, Fredholm BB (2002). Decreased inflammatory pain due to reduced carrageenan-induced inflammation in mice lacking adenosine A3 receptors. Neuroscience. 114(3): 523-7.
Pubmed
III. Wu WP, Hao JX, Halldner L, Lovdahl C, DeLander GE, Wiesenfeld-Hallin Z, Fredholm BB, Xu XJ (2005). Increased nociceptive response in mice lacking the adenosine A1 receptor. Pain. 113(3): 395-404.
Pubmed
IV. Wu WP, Hao JX, Fredholm BB, Wiesenfeld-Hallin Z, Xu XJ (2005). Effect of acute and chronic administration of caffeine on pain-like behaviors in rats with partial sciatic nerve injury. [Manuscript]
V. Wu WP, Wiesenfeld-Hallin Z, Xu XJ (2005). Strain differences in the antinociceptive effect of intrathecal R-phenylisopropyl-adenosine (R-PIA): comparison with morphine. [Manuscript]
Issue date: 2005-05-27
Publication year: 2005
ISBN: 91-7140-298-5
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