Role of peripheral sigma-1 receptors in ischaemic pain: Potential interactions with ASIC and P2X receptors.

Abstract

BACKGROUND:

The role of peripheral sigma-1 receptors (Sig-1Rs) in normal nociception and in pathologically induced pain conditions has not been thoroughly investigated. Since there is mounting evidence that Sig-1Rs modulate ischaemia-induced pathological conditions, we investigated the role of Sig-1Rs in ischaemia-induced mechanical allodynia (MA) and addressed their possible interaction with acid-sensing ion channels (ASICs) and P2X receptors at the ischaemic site.

METHODS:

We used a rodent model of hindlimb thrombus-induced ischaemic pain (TIIP) to investigate their role. Western blot was performed to observe changes in Sig-1R expression in peripheral nervous tissues. MA was measured after intraplantar (i.pl.) injections of antagonists for the Sig-1, ASIC and P2X receptors in TIIP rats or agonists of each receptor in naïve rats.

RESULTS:

Sig-1R expression significantly increased in skin, sciatic nerve and dorsal root ganglia at 3 days post-TIIP surgery. I.pl. injections of the Sig-1R antagonist, BD-1047 on post-operative days 0-3 significantly attenuated the development of MA during the induction phase, but had no effect on MA when given during the maintenance phase (days 3-6 post-surgery). BD-1047 synergistically increased amiloride (an ASICs blocker)- and TNP-ATP (a P2X antagonist)-induced analgesic effects in TIIP rats. In naïve rats, i.pl. injection of Sig-1R agonist PRE-084 alone did not produce MA; but it did induce MA when co-administered with either an acidic pH solution or a sub-effective dose of αβmeATP.

CONCLUSION:

Peripheral Sig-1Rs contribute to the induction of ischaemia-induced MA via facilitation of ASICs and P2X receptors. Thus, peripheral Sig-1Rs represent a novel therapeutic target for the treatment of ischaemic pain.

• Authors: S G Kwon, D H Roh, S Y Yoon, S R Choi, H S Choi, J Y Moon, S Y Kang, H W Kim, H J Han, A J Beitz, S B Oh, J H Lee
• Journal: European journal of pain (London, England) (Eur J Pain) Vol. 20 Issue 4 Pg. 594-606 (Apr 2016) ISSN: 1532-2149 [Electronic] England
• PMID: 26358747 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 European Pain Federation - EFIC®

Chemical References

• Acid Sensing Ion Channels
• Ethylenediamines
• Morpholines
• Receptors, Purinergic P2X
• Receptors, sigma
• 2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate
• N-(2-(3,4-Dichlorphenyl)ethyl)-N,N',N'-trimethyl-1,2-ethandiamin
• 2',3'-O-(2,4,6-trinitro-cyclohexadienylidine)adenosine 5'-triphosphate
• Adenosine Triphosphate

Topics

• Acid Sensing Ion Channels (physiology)
• Adenosine Triphosphate (analogs & derivatives)
• Animals
• Ethylenediamines
• Hindlimb (blood supply)
• Hyperalgesia (etiology, metabolism)
• Ischemia (complications, metabolism)
• Male
• Morpholines
• Pain (etiology, metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptors, Purinergic P2X (physiology)
• Receptors, sigma (physiology)
• Sigma-1 Receptor