Spinal-supraspinal serotonergic circuits regulating neuropathic pain and its treatment with gabapentin.
Not all neuropathic pain patients gain relief from current therapies that include the anticonvulsant, gabapentin, thought to modulate calcium channel function. We report a neural circuit that is permissive for the effectiveness of gabapentin. Substance P-saporin (SP-SAP) was used to selectively ablate superficial dorsal horn neurons expressing the neurokinin-1 receptor for substance P. These neurons project to the brain as shown by retrograde labelling and engage descending brainstem serotonergic influences that enhance spinal excitability via a facilitatory action on 5HT(3) receptors. We show the integrity of this pathway following nerve injury contributes to the behavioural allodynia, neuronal plasticity of deep dorsal horn neurons and the injury-specific actions of gabapentin. Thus SP-SAP attenuated the tactile and cold hypersensitivity and abnormal neuronal coding (including spontaneous activity, expansion of receptive field size) seen after spinal nerve ligation. Furthermore the powerful actions of gabapentin after neuropathy were blocked by either ablation of NK-1 expressing neurones or 5HT(3) receptor antagonism using ondansetron. Remarkably, 5HT(3) receptor activation provided a state-dependency (independent of that produced by neuropathy) allowing GBP to powerfully inhibit in normal uninjured animals. This circuit is therefore a crucial determinant of the abnormal neuronal and behavioural manifestations of neuropathy and importantly, the efficacy of gabapentin. As this spino-bulbo-spinal circuit contacts areas of the brain implicated in the affective components of pain, this loop may represent a route by which emotions can influence the degree of pain in a patient, as well as the effectiveness of the drug treatment. These hypotheses are testable in patients.
Suzuki
Rie
R
Department of Pharmacology Medical Sciences Building, University College London, Gower Street, London WC1E 6BT, UK Department of Anatomy and Developmental Biology, University College London. Gower Street, London WC1E 6BT, UK.
Rahman
Wahida
W
Rygh
Lars J
LJ
Webber
Mark
M
Hunt
Stephen P
SP
Dickenson
Anthony H
AH
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000588:Amines / Q000627:therapeutic use*; D000700:Analgesics / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects; D003509:Cyclohexanecarboxylic Acids / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D007839:Functional Laterality; D000077206:Gabapentin; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006358:Hot Temperature; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D017294:Ondansetron / Q000494:pharmacology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D011043:Pokeweed Mitogens / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism* / Q000503:physiopathology; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000627:therapeutic use*
D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D011043:Pokeweed Mitogens; D018040:Receptors, Neurokinin-1; D054789:Ribosome Inactivating Proteins, Type 1; D012702:Serotonin Antagonists; C105830:lectin B, Phytolacca americana; C468274:substance P-saporin; D012701:Serotonin; D013373:Substance P; D017294:Ondansetron; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D000076985:Saporins