Chronic activation of spinal adenosine A1 receptors results in hypersensitivity

Spinally administered adenosine reduces hypersensitivity in animals and humans with nerve injury, but also causes transient pain in humans and reduces tonic inhibition in spinal neurons. Nerve injury results in increased tonic spinal cord adenosine A1 receptor activation, consistent with a role for adenosine to generate hypersensitivity. Here, we demonstrate that chronic intrathecal adenosine induces hypersensitivity in normal animals and that chronic blockade of spinal adenosine A1 receptors by the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine partially prevents nerve injury-induced hypersensitivity. In contrast, chronic blockade of spinal adenosine A1 receptors failed to reduce increased tonic G-protein signaling in the spinal cord after nerve injury. These data support a role for chronic adenosine A1 receptor stimulation after nerve injury to result in hypersensitivity.

[1]  S. Childers,et al.  Allosteric modulation of adenosine A1 receptor coupling to G‐proteins in brain , 2005, Journal of neurochemistry.

[2]  B. Fredholm,et al.  Increased nociceptive response in mice lacking the adenosine A1 receptor , 2005, Pain.

[3]  T. Vanderah,et al.  Production of Paradoxical Sensory Hypersensitivity by &agr;2-Adrenoreceptor Agonists , 2004, Anesthesiology.

[4]  B. Fredholm,et al.  Distribution of antinociceptive adenosine a1 receptors in the spinal cord dorsal horn, and relationship to primary afferents and neuronal subpopulations , 2003, Neuroscience.

[5]  J. Eisenach,et al.  Intrathecal, but not intravenous adenosine reduces allodynia in patients with neuropathic pain , 2003, Pain.

[6]  S. Hugel,et al.  Convergent control of synaptic GABA release from rat dorsal horn neurones by adenosine and GABA autoreceptors , 2003, The Journal of physiology.

[7]  Y. Li,et al.  Adenosine suppresses the response of neurons to gaba in the superficial laminae of the rat spinal dorsal horn , 2003, Neuroscience.

[8]  T. Vanderah,et al.  Sustained Morphine Exposure Induces a Spinal Dynorphin-Dependent Enhancement of Excitatory Transmitter Release from Primary Afferent Fibers , 2002, The Journal of Neuroscience.

[9]  S. Childers,et al.  Role of Adenosine Receptors in Spinal G-Protein Activation after Peripheral Nerve Injury , 2002, Anesthesiology.

[10]  J. Eisenach,et al.  Phase I Safety Assessment of Intrathecal Injection of an American Formulation of Adenosine in Humans , 2002, Anesthesiology.

[11]  C. Luo,et al.  Adenosine inhibits excitatory transmission to substantia gelatinosa neurons of the adult rat spinal cord through the activation of presynaptic A1 adenosine receptor , 2001, Pain.

[12]  T. Vanderah,et al.  Mechanisms of opioid-induced pain and antinociceptive tolerance: descending facilitation and spinal dynorphin , 2001, Pain.

[13]  S. Childers,et al.  Chronic intrathecal morphine administration produces homologous mu receptor/G-protein desensitization specifically in spinal cord , 2001, Brain Research.

[14]  A. Dickenson,et al.  Altered effects of an A1 adenosine receptor agonist on the evoked responses of spinal dorsal horn neurones in a rat model of mononeuropathy , 2000 .

[15]  J. A. Gomes,et al.  Intrathecal adenosine interacts with a spinal noradrenergic system to produce antinociception in nerve-injured rats. , 1999, Anesthesiology.

[16]  J. Eisenach,et al.  Intrathecal adenosine: interactions with spinal clonidine and neostigmine in rat models of acute nociception and postoperative hypersensitivity. , 1999, Anesthesiology.

[17]  J. Eisenach,et al.  Exogenous and endogenous adenosine enhance the spinal antiallodynic effects of morphine in a rat model of neuropathic pain , 1999, Pain.

[18]  A. Sollevi,et al.  Intrathecal Adenosine Administration: A Phase 1 Clinical Safety Study in Healthy Volunteers, with Additional Evaluation of Its Influence on Sensory Thresholds and Experimental Pain , 1998, Anesthesiology.

[19]  D. Selley,et al.  Differences in G-protein activation by mu- and delta-opioid, and cannabinoid, receptors in rat striatum. , 1996, European journal of pharmacology.

[20]  D. Selley,et al.  In vitro autoradiography of receptor-activated G proteins in rat brain by agonist-stimulated guanylyl 5'-[gamma-[35S]thio]-triphosphate binding. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[21]  T. Yaksh,et al.  Quantitative assessment of tactile allodynia in the rat paw , 1994, Journal of Neuroscience Methods.

[22]  Jin Mo Chung,et al.  An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat , 1992, PAIN.

[23]  T. White,et al.  Classification of adenosine receptors mediating antinociception in the rat spinal cord , 1986, British journal of pharmacology.

[24]  T. Yaksh,et al.  Chronic catheterization of the spinal subarachnoid space , 1976, Physiology & Behavior.