Interplay of BDNF and GDNF in the mature spinal somatosensory system and its potential therapeutic relevance

: The growth factors BDNF and GDNF are gaining more and more attention as modulators of synaptic transmission in the mature central nervous system (CNS). The two molecules undergo a regulated secretion in neurons and may be anterogradely transported to terminals where they can positively or negatively modulate fast synaptic transmission. There is today wide consensus on the role of BDNF as a pro-nociceptive modulator, as the neurotrophin has an important part in the initiation and maintenance of inflammatory, chronic, and/or neuropathic pain at peripheral and central level. At spinal level, BDNF intervenes in the regulation of chloride equilibrium potential, decreases the excitatory synaptic drive to inhibitory neurons, with complex changes in GABAergic/glycinergic synaptic transmission, and increases excitatory transmission in the superficial dorsal horn. Differently from BDNF, the role of GDNF still remains to be unraveled in full. This review resumes the current literature on the interplay between BDNF and GDNF in the regulation of nociceptive neurotransmission in the superficial dorsal horn of the spinal cord. We will first discuss the circuitries involved in such a regulation, as well as the reciprocal interactions between the two factors in nociceptive pathways. The development of small molecules specifically targeting BDNF, GDNF and/or downstream effectors is opening new perspectives for investigating these neurotrophic factors as modulations of nociceptive transmission and chronic pain. Therefore, we finally will consider the molecules of (potential) pharmacological relevance for tackling normal and pathological pain.

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Role of 5-HT1receptor subtypes in the modulation of pain and synaptic transmission in rat spinal superficial dorsal horn

British Journal of Pharmacology ◽

10.1111/j.1476-5381.2011.01685.x ◽

2012 ◽

Vol 165 (6) ◽

pp. 1956-1965 ◽

Cited By ~ 39

Author(s):

Hyo-Jin Jeong ◽

Vanessa A Mitchell ◽

Christopher W Vaughan

Keyword(s):

Synaptic Transmission ◽

Dorsal Horn ◽

Superficial Dorsal Horn

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Modulation of excitatory synaptic transmission by nociceptin in superficial dorsal horn neurones of the neonatal rat spinal cord

British Journal of Pharmacology ◽

10.1038/sj.bjp.0701149 ◽

1997 ◽

Vol 121 (3) ◽

pp. 425-432 ◽

Cited By ~ 97

Author(s):

Jörg T. Liebel ◽

Dieter Swandulla ◽

Hanns Ulrich Zeilhofer

Keyword(s):

Spinal Cord ◽

Synaptic Transmission ◽

Dorsal Horn ◽

Excitatory Synaptic Transmission ◽

Neonatal Rat ◽

Superficial Dorsal Horn ◽

Rat Spinal Cord ◽

Dorsal Horn Neurones

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The excitability of dorsal horn neurons is affected by cerebrospinal fluid from humans with osteoarthritis

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y2012-014 ◽

2012 ◽

Vol 90 (6) ◽

pp. 783-790

Author(s):

Van B. Lu ◽

Peter A. Smith ◽

Saifee Rashiq

Keyword(s):

Synaptic Transmission ◽

Dorsal Horn ◽

Sensory Processing ◽

Human Subjects ◽

Substantia Gelatinosa ◽

Inhibitory Neurons ◽

Membrane Properties ◽

Electrophysiological Properties ◽

Osteoarthritis Pain ◽

Cultured Slices

Changes in central neural processing are thought to contribute to the development of chronic osteoarthritis pain. This may be reflected as the presence of inflammatory mediators in the cerebral spinal fluid (CSF). We therefore exposed organotypically cultured slices of rat spinal cord to CSF from human subjects with osteoarthritis (OACSF) at a ratio of 1 part CSF in 9 parts culture medium for 5–6 days, and measured changes in neuronal electrophysiological properties by means of whole-cell recording. Although OACSF had no effect on the membrane properties and excitability of neurons in the substantia gelatinosa, synaptic transmission was clearly altered. The frequency of spontaneous excitatory postsynaptic currents (sEPSC) in delay-firing putative excitatory neurons was increased, as was sEPSC amplitude and frequency in tonic-firing inhibitory neurons. These changes could affect sensory processing in the dorsal horn, and may affect the transfer of nociceptive information. Although OACSF also affected inhibitory synaptic transmission (frequency of spontaneous inhibitory synaptic currents; sIPSC), this may have little bearing on sensory processing by substantia gelatinosa neurons, as sEPSC frequency is >3× greater than sIPSC frequency in this predominantly excitatory network. These results support the clinical notion that changes in nociceptive processing at the spinal level contribute to the generation of chronic osteoarthritis pain.

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Role of prostaglandin receptor subtype EP1 in prostaglandin E2-induced nociceptive transmission in the rat spinal dorsal horn

Brain Research ◽

10.1016/j.brainres.2004.03.002 ◽

2004 ◽

Vol 1010 (1-2) ◽

pp. 62-68 ◽

Cited By ~ 31

Author(s):

Yoshito Nakayama ◽

Keiichi Omote ◽

Tomoyuki Kawamata ◽

Akiyoshi Namiki

Keyword(s):

Prostaglandin E2 ◽

Dorsal Horn ◽

Spinal Dorsal Horn ◽

Receptor Subtype ◽

Nociceptive Transmission ◽

Prostaglandin Receptor ◽

Spinal Dorsal

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Opioid Tolerance and Physical Dependence: Role of Spinal Neuropeptides, Excitatory Amino Acids and Their Messengers

Pain Research and Management ◽

10.1155/2000/959161 ◽

2000 ◽

Vol 5 (1) ◽

pp. 25-32 ◽

Cited By ~ 5

Author(s):

Khem Jhamandas ◽

Kelly Powell ◽

Remi Quirion ◽

B Milne

Keyword(s):

Nitric Oxide ◽

Amino Acid ◽

Dorsal Horn ◽

Excitatory Amino Acid ◽

Physical Dependence ◽

Opioid Tolerance ◽

Opioid Agonist ◽

Nociceptive Transmission ◽

Neuropeptide Ff

Chronic opioid treatment results in the development of tolerance and physical dependence. The mechanisms underlying opioid tolerance and/or physical dependence are unclear. Recent studies suggest that opioid receptor or nociceptive, neural network-based adaptations contribute to this phenomenon. At the spinal level, the genesis of tolerance and physical dependence is associated with increased excitatory amino acid activity expressed throughN-methyl-D-aspartate receptors in the dorsal horn. However, recent evidence also implicates spinal neuropeptide transmitters such as calcitonin gene-related peptide (CGRP) and substance P in the development of opioid tolerance. Long term spinal morphine treatment increases CGRP-like immunostaining in the dorsal horn, and coadministration of morphine with CGRP8-37, a competitive CGRP1receptor antagonist, prevents this response as well as loss of the analgesic potency. CGRP8-37, likeN-methyl-D-aspartate receptor antagonists, has the potential to restore morphine potency in experimental animals who are already tolerant to the opioid agonist. Recent evidence suggests that the effects of excitatory amino acid and neuropeptide receptor activity may be expressed through the generation of messengers such as nitric oxide and prostanoids. Agents that inhibit the synthesis of nitric oxide and prostanoids have the potential to inhibit and reverse spinal opioid tolerance, suggesting that this phenomenon may be expressed through the activity of these mediators. Nociceptive transmission in the dorsal horn of the spinal cord also involves activity of a number of other mediators including morphine modulatory neuropeptides, neuropeptide FF and neuropeptide SF. The role of these mediators and their relationship with other factors implicated in tolerance remain to be determined.

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