Intrathecal clonidine reduces hypersensitivity after nerve injury by a mechanism involving spinal m4 muscarinic receptors.
alpha2-Adrenergic agonists reduce mechanical and thermal hypersensitivity in animals with nerve injury and effectively treat neuropathic pain in humans. Previous studies indicate a reliance of alpha2-adrenergic agonists in this setting on spinal cholinergic activation and stimulation of muscarinic receptors. The subtype(s) of muscarinic receptors in the spinal cord that produces antinociception in normal animals is controversial, and those involved in reducing hypersensitivity and interacting with alpha2-adrenergic systems after nerve injury are unstudied. To examine this, the left L5 and L6 spinal nerves were tightly ligated in rats, resulting in reduction in withdrawal threshold to punctate mechanical stimuli. Intrathecal clonidine, 15 micro g, returned the withdrawal threshold to normal. Using highly specific m1 and m4 antagonists, we observed no reduction in the effect of clonidine by the m1 antagonist, but inhibition of clonidine's effect by the m4 antagonist. Western analysis revealed no difference in quantitative expression of m1 and m4 receptor protein in the dorsal spinal cord of spinal nerve-injured animals compared with sham-operated controls, suggesting this interaction with m4 receptors does not reflect an increase in receptor expression.


CONCLUSIONS
Neuraxial clonidine is an effective adjunct in the treatment of neuropathic pain and increases acetylcholine concentrations in cerebrospinal fluid in humans. These data in animals suggest that spinal m4 type muscarinic receptors are important to the effect of clonidine in treating hypersensitivity to touch after nerve injury.
Kang
Yoo-Jin
YJ
Department of Anesthesiology and Center for the Study of Pharmacologic Plasticity in the Presence of Pain, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
Eisenach
James C
JC
D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D003000:Clonidine / Q000008:administration & dosage / Q000494:pharmacology*; D004546:Elapid Venoms / Q000494:pharmacology; D017815:Elapidae; D007278:Injections, Spinal; D008026:Ligation; D008297:Male; D008465:Mechanoreceptors / Q000187:drug effects / Q000502:physiology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000187:drug effects; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000293:injuries / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D004546:Elapid Venoms; D018727:Muscarinic Antagonists; D043588:Receptor, Muscarinic M4; D011976:Receptors, Muscarinic; D003000:Clonidine