Chronic neuropathic pain is a debilitating ordeal for patients worldwide and pharmacological treatment efficacy is still limited. As many pharmacological interventions for neuropathic pain often fail, insights into the underlying mechanism and role of identified receptors is of utmost importance. An important target for improving treatment of neuropathic pain is the descending serotonergic system as these projections modulate nociceptive signaling in the dorsal horn. Also with use of last resort treatments like spinal cord stimulation (SCS), the descending serotonergic projections are known to be involved in the pain relieving effect. This systematic review summarizes the involvement of the serotonergic system on nociceptive modulation in the healthy adult rodent and the chronic neuropathic rodent and summarizes all available literature on the serotonergic system in the SCS-treated neuropathic rodent. Medline, Embase and Pubmed databases were used in the search for articles. Descending serotonergic modulation of nociceptive signaling in spinal dorsal horn in normal adult rat is mainly inhibitory and mediated by 5-HT1a, 5-HT1b, 5-HT2c, 5-HT3 and 5-HT4 receptors. Upon injury and in the neuropathic rat, this descending serotonergic modulation becomes facilitatory via activation of the 5-HT2a, 5-HT2b and 5-HT3 receptors. Analgesia due to neuromodulatory intervention like SCS restores the inhibitory function of the descending serotonergic system and involves 5-HT2, 5-HT3 and 5-HT4 receptors. The results of this systematic review provide insights and suggestions for further pharmacological and or neuromodulatory treatment of neuropathic pain based on targeting selected serotonergic receptors related to descending modulation of nociceptive signaling in spinal dorsal horn. With the novel developed SCS paradigms, the descending serotonergic system will be an important target for mechanism-based stimulation induced analgesia.

The N-methyl-D-aspartate receptor (NMDAR) is an important mediator of central sensitization and nociception in the rat spinal dorsal horn. The NMDAR subunits and splice variants determine the properties of the receptor. Understanding the expression of NMDAR subunits in spinal cord during the neonatal development is important as it may have consequences for the process of central sensitization and nociception in later life. In this review, a systematic literature search was conducted using three databases: Medline, Embase, and PubMed. A quality assessment was performed on predetermined entities of bias. Thirteen articles were identified to be relevant. The results show that NMDAR subunits and splice variants are dynamically expressed during postnatal development in the spinal dorsal horn. During the first 2 weeks, the expression of less excitable GluN2A subunit and more sensitive GluN2B subunit increases while the expression of high excitable GluN2C subunit decreases. During the 2nd week of postnatal development GluN1 subunits with exon 21 spliced in but exon 22 spliced out are predominantly expressed, increasing phosphorylation, and transport to the membrane. The data suggest that in rats, the nociceptive system is most susceptible to central sensitization processes during the first two postnatal weeks. This may have important consequences for nociception and pain responses in later life. From this, we conclude that targeted therapy directed toward specific NMDAR subunits is a promising candidate for mechanism-based treatment of pain in neonates.

BACKGROUND: Burst spinal cord stimulation (SCS) technology uses a novel waveform that consists of closely packed high-frequency electrical impulses followed by a quiescent period. Within the growing field of neuromodulation, burst stimulation is unique in that it mimics the natural burst firing of the nervous system, in particular the thalamo-cingulate rhythmicity, resulting in modulation of the affective and attentional components of pain processing (e.g., medial thalamic pathways).
METHODS: A review of preclinical and clinical studies regarding burst SCS for various chronic pain states.
METHODS: Available literature was reviewed on burst stimulation technology. Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles.
METHODS: The primary outcome measure was to understand the mechanisms of action with regards to burst stimulation and to review clinical data on the indications of burst SCS for various chronic pain states.
RESULTS: We present both mechanisms of action and review uses of burst stimulation for various pain states.
CONCLUSIONS: Burst stimulation offers a novel pain reduction tool with the absence of uncomfortable paresthesia for failed back surgery syndrome, diabetic neuropathic pain, and anesthesia dolorosa. Preclinical models have emphasized that the potential mechanisms for burst therapy could be related to neural coding algorithms that mimic the natural nervous system firing patterns, resulting in effects on both the medial and lateral pain pathways. Other mechanisms include frequency dependent opioid release, modulation of the pain gate, and activation of electrical and chemical synapses.