Mice Lacking Central Serotonergic Neurons Show Enhanced Inflammatory Pain and an Impaired Analgesic Response to Antidepressant Drugs

A large body of literature has implicated serotonin [5-hydroxytryptamine (5-HT)] in descending modulation of nociceptive transmission. Here, we have studied the pain behavior of Lmx1b conditional knock-out mice (Lmx1bf/f/p), which lack 5-HT neurons in the CNS. Lmx1bf/f/p mutant mice showed normal thermal and visceral pain responses but were less sensitive to mechanical stimuli and exhibited enhanced inflammatory pain compared with their littermate control mice. Importantly, the analgesic effect of several antidepressant drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants, was either abolished or greatly attenuated in Lmx1bf/f/p mice. Moreover, in the acute versus persistent pain settings, the analgesic actions of the SNRI duloxetine and the SSRI fluoxetine were differentially affected. Together, our results provide in vivo genetic evidence demonstrating that although the predominant role of the central 5-HT system in inflammatory pain is inhibitory, its role in acute mechanical pain is facilitatory. The findings that the analgesic effects of various antidepressant drugs are differentially dependent on the central 5-HT system should help us to understand the mechanism of the analgesic action of different classes of antidepressants in the management of persistent pain.

[1]  E. Deneris,et al.  Lmx1b Is Required for Maintenance of Central Serotonergic Neurons and Mice Lacking Central Serotonergic System Exhibit Normal Locomotor Activity , 2006, The Journal of Neuroscience.

[2]  J. Mikkelsen,et al.  Antinociceptive effects of the antidepressants amitriptyline, duloxetine, mirtazapine and citalopram in animal models of acute, persistent and neuropathic pain , 2005, Neuropharmacology.

[3]  M. Esser,et al.  Antidepressants as analgesics: an overview of central and peripheral mechanisms of action. , 2001, Journal of psychiatry & neuroscience : JPN.

[4]  D. Fishbain,et al.  Evidence-based data from animal and human experimental studies on pain relief with antidepressants: a structured review. , 2000, Pain medicine.

[5]  A. Dickenson,et al.  Does a Single Intravenous Injection of the 5HT3 Receptor Antagonist Ondansetron Have an Analgesic Effect in Neuropathic Pain? A Double-Blinded, Placebo-Controlled Cross-Over Study , 2003, Anesthesia and analgesia.

[6]  S. Iyengar,et al.  Efficacy of Duloxetine, a Potent and Balanced Serotonin-Norepinephrine Reuptake Inhibitor in Persistent Pain Models in Rats , 2004, Journal of Pharmacology and Experimental Therapeutics.

[7]  E. Deneris,et al.  Lmx1b is essential for the development of serotonergic neurons , 2003, Nature Neuroscience.

[8]  M. Durieux,et al.  Antidepressants as Long-Acting Local Anesthetics , 2003, Regional Anesthesia & Pain Medicine.

[9]  R. Dubner,et al.  A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia , 1987, Pain.

[10]  G. Wang,et al.  State-dependent block of voltage-gated Na+ channels by amitriptyline via the local anesthetic receptor and its implication for neuropathic pain , 2004, Pain.

[11]  R Dubner,et al.  Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. , 1992, The New England journal of medicine.

[12]  Rie Suzuki,et al.  Bad news from the brain: descending 5-HT pathways that control spinal pain processing. , 2004, Trends in pharmacological sciences.

[13]  T. Jensen,et al.  Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action , 1999, PAIN®.

[14]  S. Hunt,et al.  Superficial NK1-expressing neurons control spinal excitability through activation of descending pathways , 2002, Nature Neuroscience.

[15]  H. Fields,et al.  Peptidergic Nociceptors of Both Trigeminal and Dorsal Root Ganglia Express Serotonin 1D Receptors: Implications for the Selective Antimigraine Action of Triptans , 2003, The Journal of Neuroscience.

[16]  K. Lawson.  Tricyclic antidepressants and fibromyalgia: what is the mechanism of action? , 2002, Expert opinion on investigational drugs.

[17]  P. Wiffen,et al.  Antidepressants and anticonvulsants for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. , 2000, Journal of pain and symptom management.

[18]  M. Urban,et al.  Supraspinal contributions to hyperalgesia. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Brandão.  Serotonin and pain , 1991 .

[20]  J. Wernicke,et al.  A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain , 2006, Neurology.

[21]  A I Basbaum,et al.  Endogenous pain control systems: brainstem spinal pathways and endorphin circuitry. , 1984, Annual review of neuroscience.

[22]  C. Epstein,et al.  Primary afferent tachykinins are required to experience moderate to intense pain , 1998, Nature.

[23]  F. Benes,et al.  Neonatal raphe lesions increase dopamine fibers in prefrontal cortex of adult rats , 1998, Neuroreport.

[24]  A. Eschalier,et al.  Serotonin receptor subtypes involved in the spinal antinociceptive effect of 5-HT in rats , 2000, Pain.

[25]  D. Groves.  Antidepressants as local anesthetics: is there a place in regional anesthesia? , 2006, Current opinion in anaesthesiology.

[26]  S. Stahl,et al.  Understanding pain in depression , 2004, Human psychopharmacology.

[27]  D. Julius,et al.  The capsaicin receptor: a heat-activated ion channel in the pain pathway , 1997, Nature.

[28]  M. Maizels,et al.  Antidepressants and antiepileptic drugs for chronic non-cancer pain. , 2005, American family physician.

[29]  P. Mason,et al.  Neurotransmitters in nociceptive modulatory circuits. , 1991, Annual review of neuroscience.

[30]  P. K. Dey,et al.  Probable involvement of serotonin in the increased permeability of the blood—brain barrier by forced swimming. An experimental study using Evans blue and 131I-sodium tracers in the rat , 1995, Behavioural Brain Research.

[31]  J. Lauder,et al.  In utero exposure to serotonergic drugs alters neonatal expression of 5-HT1A receptor transcripts: a quantitative RT-PCR study , 2000, International Journal of Developmental Neuroscience.

[32]  A. Eschalier,et al.  Antidepressants and pain. , 2006, Trends in pharmacological sciences.

[33]  A I Basbaum,et al.  Brainstem control of spinal pain-transmission neurons. , 1978, Annual review of physiology.

[34]  M. Lynch.  Antidepressants as analgesics: a review of randomized controlled trials. , 2001, Journal of psychiatry & neuroscience : JPN.

[35]  P. Mason,et al.  Contributions of the medullary raphe and ventromedial reticular region to pain modulation and other homeostatic functions. , 2001, Annual review of neuroscience.

[36]  Nathan Chandler,et al.  Corticotropin-Releasing Hormone and Brain Mast Cells Regulate Blood-Brain-Barrier Permeability Induced by Acute Stress , 2002, Journal of Pharmacology and Experimental Therapeutics.

[37]  M. Briley.  Clinical experience with dual action antidepressants in different chronic pain syndromes , 2004, Human psychopharmacology.

[38]  Rie Suzuki,et al.  Descending facilitatory control of mechanically evoked responses is enhanced in deep dorsal horn neurones following peripheral nerve injury , 2004, Brain Research.

[39]  M. Ansorge,et al.  New Lessons From Knockout Mice: The Role of Serotonin During Development and Its Possible Contribution to the Origins of Neuropsychiatric Disorders , 2003, CNS Spectrums.

[40]  Stanley Jacobson,et al.  Acute stress increases permeability of the blood–brain-barrier through activation of brain mast cells , 2001, Brain Research.

[41]  H. Shannon,et al.  Efficacy of Duloxetine, a Potent and Balanced Serotonergic and Noradrenergic Reuptake Inhibitor, in Inflammatory and Acute Pain Models in Rodents , 2005, Journal of Pharmacology and Experimental Therapeutics.

[42]  L. Weaver,et al.  The 5-HT3 receptor facilitates at-level mechanical allodynia following spinal cord injury , 2004, Pain.

[43]  S. Hunt,et al.  Depletion of endogenous spinal 5-HT attenuates the behavioural hypersensitivity to mechanical and cooling stimuli induced by spinal nerve ligation , 2006, PAIN.

[44]  J. Stamford.  Descending control of pain. , 1995, British journal of anaesthesia.

[45]  M. Zhuo,et al.  Spinal serotonin receptors mediate descending facilitation of a nociceptive reflex from the nuclei reticularis gigantocellularis and gigantocellularis pars alpha in the rat , 1991, Brain Research.

[46]  Vijay P. Singh,et al.  On the antinociceptive effect of fluoxetine, a selective serotonin reuptake inhibitor , 2001, Brain Research.

[47]  M. Biasi,et al.  Corelease of Dopamine and Serotonin from Striatal Dopamine Terminals , 2005, Neuron.

[48]  Kjell Hole,et al.  The formalin test in mice: dissociation between inflammatory and non-inflammatory pain , 1987, Pain.