Endogenous adenosine A<inf>3</inf> receptor activation selectively alleviates persistent pain states

Joshua W. Little, Amanda Ford, Ashley M. Symons-Liguori, Zhoumou Chen, Kali Janes, Timothy Doyle, Jennifer Xie, Livio Luongo, Dillip K. Tosh, Sabatino Maione, Kirsty Bannister, Anthony H. Dickenson, Todd W Vanderah, Frank Porreca, Kenneth A. Jacobson, Daniela Salvemini

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

Chronic pain is a global burden that promotes disability and unnecessary suffering. To date, efficacious treatment of chronic pain has not been achieved. Thus, new therapeutic targets are needed. Here, we demonstrate that increasing endogenous adenosine levels through selective adenosine kinase inhibition produces powerful analgesic effects in rodent models of experimental neuropathic pain through the A<inf>3</inf> adenosine receptor (A<inf>3</inf>AR, now known as ADORA3) signalling pathway. Similar results were obtained by the administration of a novel and highly selective A<inf>3</inf>AR agonist. These effects were prevented by blockade of spinal and supraspinal A<inf>3</inf>AR, lost in A<inf>3</inf>AR knock-out mice, and independent of opioid and endocannabinoid mechanisms. A<inf>3</inf>AR activation also relieved non-evoked spontaneous pain behaviours without promoting analgesic tolerance or inherent reward. Further examination revealed that A<inf>3</inf>AR activation reduced spinal cord pain processing by decreasing the excitability of spinal wide dynamic range neurons and producing supraspinal inhibition of spinal nociception through activation of serotonergic and noradrenergic bulbospinal circuits. Critically, engaging the A<inf>3</inf>AR mechanism did not alter nociceptive thresholds in non-neuropathy animals and therefore produced selective alleviation of persistent neuropathic pain states. These studies reveal A<inf>3</inf>AR activation by adenosine as an endogenous anti-nociceptive pathway and support the development of A<inf>3</inf>AR agonists as novel therapeutics to treat chronic pain.

Original languageEnglish (US)
Pages (from-to)28-35
Number of pages8
JournalBrain
Volume138
Issue number1
DOIs
StatePublished - Dec 11 2013

Fingerprint

Adenosine A3 Receptors
Chronic Pain
Neuralgia
Pain
Adenosine
Analgesics
Adenosine Kinase
Endocannabinoids
Nociception
Reward
Psychological Stress
Knockout Mice
Opioid Analgesics
Rodentia
Spinal Cord
Theoretical Models
Therapeutics
Neurons
Activation
Inhibition (Psychology)

Keywords

  • A<inf>3</inf>AR
  • Adenosine
  • Chronic pain
  • Rostral ventromedial medulla
  • Spontaneous pain

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Little, J. W., Ford, A., Symons-Liguori, A. M., Chen, Z., Janes, K., Doyle, T., ... Salvemini, D. (2013). Endogenous adenosine A<inf>3</inf> receptor activation selectively alleviates persistent pain states. Brain, 138(1), 28-35. https://doi.org/10.1093/brain/awu330

Endogenous adenosine A<inf>3</inf> receptor activation selectively alleviates persistent pain states. / Little, Joshua W.; Ford, Amanda; Symons-Liguori, Ashley M.; Chen, Zhoumou; Janes, Kali; Doyle, Timothy; Xie, Jennifer; Luongo, Livio; Tosh, Dillip K.; Maione, Sabatino; Bannister, Kirsty; Dickenson, Anthony H.; Vanderah, Todd W; Porreca, Frank; Jacobson, Kenneth A.; Salvemini, Daniela.

In: Brain, Vol. 138, No. 1, 11.12.2013, p. 28-35.

Research output: Contribution to journalArticle

Little, JW, Ford, A, Symons-Liguori, AM, Chen, Z, Janes, K, Doyle, T, Xie, J, Luongo, L, Tosh, DK, Maione, S, Bannister, K, Dickenson, AH, Vanderah, TW, Porreca, F, Jacobson, KA & Salvemini, D 2013, 'Endogenous adenosine A<inf>3</inf> receptor activation selectively alleviates persistent pain states', Brain, vol. 138, no. 1, pp. 28-35. https://doi.org/10.1093/brain/awu330
Little JW, Ford A, Symons-Liguori AM, Chen Z, Janes K, Doyle T et al. Endogenous adenosine A<inf>3</inf> receptor activation selectively alleviates persistent pain states. Brain. 2013 Dec 11;138(1):28-35. https://doi.org/10.1093/brain/awu330
Little, Joshua W. ; Ford, Amanda ; Symons-Liguori, Ashley M. ; Chen, Zhoumou ; Janes, Kali ; Doyle, Timothy ; Xie, Jennifer ; Luongo, Livio ; Tosh, Dillip K. ; Maione, Sabatino ; Bannister, Kirsty ; Dickenson, Anthony H. ; Vanderah, Todd W ; Porreca, Frank ; Jacobson, Kenneth A. ; Salvemini, Daniela. / Endogenous adenosine A<inf>3</inf> receptor activation selectively alleviates persistent pain states. In: Brain. 2013 ; Vol. 138, No. 1. pp. 28-35.
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