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Spinal nociception can be facilitated by 5-HT2 receptors in neuropathic pain. We investigated the involvement of glutamate receptors in dorsal neuron hyperexcitation that is promoted by 5-HT2B receptor (5-HT2BR) after spinal nerve ligation (SNL) in the rat. Augmentation of C-fiber-evoked potentials by spinal superfusion with 5-HT2BR agonist BW 723C86 in nerve-ligated rats was impeded by co-administration of NMDA receptor (NMDAR) antagonist D-AP5, but not by mGluR1/5 antagonist AIDA or mGluR2/3 antagonist LY 341495. Evoked potentials were increased by cis-ACPD in nerve-injured rats, irrespective of simultaneous 5-HT2BR blockade by SB204741. In uninjured rats, NMDAR agonist cis-ACPD enhanced evoked potentials in the presence of BW 723C86 but not if administered alone or during exposure to protein kinase C γ (PKCγ) inhibitor peptide. Triple immunofluorescence labelings revealed co-localization of NMDAR and 5-HT2BR in PKCγ-expressing perikarya in lamina II neurons. As a result of SNL, PKCγ was transiently and bilaterally up-regulated in synaptic fraction from dorsal horn homogenates, peaking at day 2 and returning to basal levels by day 9. Chronic blockade of 5-HT2BR with selective antagonist SB 204741 after SNL bilaterally decreased the following: (i) PKCγ up-regulation in synaptic fraction, (ii) phosphorylation of NMDAR subunit NR1 (serine 889) in synaptic fraction, and (iii) co-localization of both PKCγ and phosphorylated NR1 with postsynaptic marker PSD-95. Chronic delivery of SB 204741 bilaterally attenuated thermal and mechanical allodynia occurring after SNL, particularly at day 2 post injury. These findings suggest that transient activation of the PKCγ/NMDAR pathway is critically involved in 5-HT2BR-mediated facilitation in the SNL model of neuropathic pain.

Fibromyalgia syndrome (FMS) is a highly prevalent, chronic musculoskeletal condition characterized by widespread pain and evoked pain at tender points. This study evaluated various aspects of body awareness in a sample of 14 women with FMS and 13 healthy controls, such as plasticity of the body schema, body esteem, and interoceptive awareness. To this end, the Rubber Hand Illusion (RHI), the Body Esteem Scale (BES), and the Body Perception Questionnaire (BPQ) were used, respectively. Consistent with increased plasticity of the body schema, FMS patients scored higher, with large or very large effect sizes, across all three domains evaluated in the RHI paradigm, namely proprioceptive drift and perceived ownership and motor control over the rubber hand. Scores on all items addressed by the BES were consistently lower among FMS subjects (2.52, SEM .19 vs 3.89, SEM .16, respectively, p < .01, Cohen’s d = .38-.66). In the FMS sample, BES scores assigned to most painful regions also were lower than those assigned to the remaining body sites (1.58, SEM .19 vs 2.87, SEM .18, respectively, p < .01). Significantly higher scores (p < .01, Cohen’s d = .51-.87) were found in the FMS sample across awareness (3.57 SEM .15 vs 1.87 SEM .11), stress response (3.76 SEM .11 vs 1.78 SEM .11), autonomic nervous system reactivity (2.59 SEM .17 vs 1.35 SEM .07), and stress style 2 (2.73 SEM .27 vs 1.13 SEM .04) subscales of the BPQ. Intensity of ongoing clinical pain was found to be strongly correlated with interoceptive awareness (r = .75, p = .002). The results suggest a disturbed embodiment in FMS, characterized by instability of the body schema, negatively biased cognitions regarding one’s own body, and increased vigilance to internal bodily cues. These manifestations may be interpreted as related with the inability of incoming sensory inputs to adequately update negatively biased off-line somatorepresentations stored as long-term memory.

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Opioid analgesia is compromised by intracellular mediators such as protein kinase C (PKC). The phosphatidylinositol hydrolysis-coupled serotonin receptor 5-HT2 is ideally suited to promote PKC activation. We test the hypothesis that 5-HT2A and 5-HT2B receptors, which have been previously shown to become pro-excitatory after spinal nerve ligation (SNL), can negatively influence the ability of opioids to depress spinal excitation evoked by noxious input. Spinal superfusion with (100 nM) mu-opioid receptor (MOR)-agonist DAMGO significantly depressed C fiber-evoked spinal field potentials. Simultaneous administration of subclinical 5-HT2AR antagonist 4F 4PP (100 nM) or 5-HT2BR antagonist SB 204741 (100 nM) significantly reduced the IC50 value for DAMGO in nerve-ligated rats (97.56 nM ± 1.51 and 1.20 nM ± 1.28 respectively, relative to 104 nM ± 1.08 at the baseline condition), but not in sham-operated rats. Both antagonists failed to alter depression induced by delta-opioid receptor (DOR)-agonist D-ala2-deltorphin II after SNL as well as in the sham condition. Western blot analysis of dorsal horn homogenates revealed bilateral upregulation of 5-HT2AR and 5-HT2BR protein band densities after SNL. As assessed from double immunofluorescence labeling for confocal laser scanning microscopy, scarce dorsal horn cell processes showed co-localization color overlay for 5-HT2AR/MOR, 5-HT2BR/MOR, 5-HT2AR/DOR, or 5-HT2BR/DOR in sham-operated rats. Intensity correlation-based analyses showed significant increases in 5-HT2AR/MOR and 5-HT2BR/MOR co-localizations after SNL. These results indicate that plasticity of spinal serotonergic neurotransmission can selectively reduce spinal MOR mechanisms via 5-HT2A and 5-HT2B receptors, including upregulation of the latter and increased expression in dorsal horn neurons containing MOR.

A sound strategy for improving the clinical efficacy of opioids involves exploiting positive interactions with drugs directed at other targets in pain pathways. The current study investigated the role of dopamine receptor D2 (D2R) in modulation of spinal dorsal horn excitability to noxious input, and interactions therein with μ-opioid receptor (MOR) in an animal model of neuropathic pain induced by spinal nerve ligation (SNL). C-fiber-evoked field potentials in the spinal dorsal horn were depressed concentration dependently by spinal superfusion with the D2R agonist quinpirole both in nerve-injured and sham-operated (control) rats. However, quinpirole-induced depression was significant at 10 μmol/L after SNL but only at 100 μmol/L in control rats. This quinpirole effect was completely abolished by MOR antagonist CTOP at subclinical concentration (1 μmol/L) in nerve-injured rats, but was unaltered in sham-operated rats. Nine days after SNL, D2R was upregulated to both presynaptic and postsynaptic locations in dorsal horn neurons, as revealed by double confocal immunofluorescence stainings for synaptophysin and PSD-95. In addition, D2R/MOR co-localization was increased after SNL. Co-administration of 1 μmol/L quinpirole, insufficient per se to alter evoked potentials, dramatically enhanced inhibition of evoked potentials by MOR agonist DAMGO, reducing the IC50 value of DAMGO by 2 orders of magnitude. The present data provide evidence of profound functional and subcellular changes in D2R-mediated modulation of noxious input after nerve injury, including positive interactions with spinal MOR. These results suggest D2R co-stimulation as a potential avenue to improve MOR analgesia in sustained pain states involving peripheral nerve injury.

Objective: Evidence suggests that there is an association between chronic pain and disruption of the body schema. We tested the hypothesis in fibromyalgia syndrome (FMS). Materials and Methods: We investigated distinct perceptual aspects of the body schema both in a sample of patients with FMS and in pain-free controls. Performances on the left/right judgment task were measured; tactile acuity was assessed by using the 2-point discrimination test. Furthermore, we evaluated sensations evoked by tactile stimulation with von Frey filaments to body parts that were experiencing pain. Anomalous sensations elicited by sensory-motor conflict (SMC) were also investigated. Results: Patients with FMS showed inferior performance on the right/left judgment task, both in terms of correct matches (75.38% vs. 89.67%, respectively; P<0.05) and response time (2.58 s vs. 1.89 s, respectively; P<0.05). Effect sizes were large and very large, respectively. Two-point discrimination thresholds were significantly higher (P<0.05) in participants from the FMS sample (mean of 49.71 mm, SD: 12.09 mm) relative to controls (mean of 37.36 mm, SD: 7.81 mm). Nine of 14 participants with FMS, but no control participants, reported referred sensations upon tactile stimulation, including tingling, pins and needles, weight, and cramps. Referral sites included regions both adjacent and remote to stimulated sites. Patients with FMS scored across all items within the administered questionnaire addressing anomalous sensations on the mirror setup (Cohen d=1.04 to 2.42 across all items), and FMS patients perceived pain during the SMC (the required statistical power for it to be statistically significant was 96% and for it to be recognized as a difference of means in pain item). Conclusion: Our present findings suggest a disrupted body schema and propensity to experiencing anomalous somatosensory sensations during SMC in people with FMS.