Role of 5-HT1A-mediated upregulation of brain indoleamine 2,3 dioxygenase 1 in the reduced antidepressant and antihyperalgesic effects of fluoxetine during maintenance treatment.

The reduced antidepressant and antihyperalgesic effects of selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine during maintenance treatment has been reported, but little is known about the molecular mechanism of this phenomenon. In three comorbid pain and depression animal models (genetic predisposition, chronic social stress, arthritis), we showed that the fluoxetine's antidepressant and antihyperalgesic effects were reduced during the maintenance treatment. Fluoxetine exposure induced upregulation of the 5-hydroxytryptamine 1A (5-HT1A) auto-receptor and indoleamine 2,3 dioxygenase 1 (IDO1, a rate-limiting enzyme of tryptophan metabolism) in the brainstem dorsal raphe nucleus (DRN), which shifted the tryptophan metabolism away from the 5-HT biosynthesis. Mechanistically, IDO1 upregulation was downstream to fluoxetine-induced 5-HT1A receptor expression because 1) antagonism of the 5-HT1A receptor with WAY100635 or 5-HT1A receptor knockout blocked the IDO1 upregulation, and 2) inhibition of IDO1 activity did not block the 5-HT1A receptor upregulation following fluoxetine exposure. Importantly, inhibition of either the 5-HT1A receptor or IDO1 activity sustained the fluoxetine's antidepressant and antihyperalgesic effects, indicating that 5-HT1A-mediated IDO1 upregulation in the brainstem DRN contributed to the reduced antidepressant and antihyperalgesic effects of fluoxetine. These results suggest a new strategy to improving the therapeutic efficacy of SSRI during maintenance treatment.

Comparison between acupuncture therapy and gabapentin for chronic pain: a pilot study.

BACKGROUND: We examined whether the effect of true electroacupuncture on pain and functionality in chronic pain participants can be differentiated from that of medication (gabapentin) by analyzing quantitative sensory testing (QST). METHODS: We recruited chronic back and neck pain participants who received six sessions (twice weekly) of true electroacupuncture versus sham electroacupuncture or 3 weeks of gabapentin versus placebo treatment. QST profiles, pain scores, and functionality profile were obtained at baseline (visit 1) and after three sessions (visit 4) or six sessions (visit 7) of acupuncture or 3 weeks of gabapentin or placebo. RESULTS: A total of 50 participants were analyzed. We found no differences in QST profile changes (p = 0.892), pain reduction (p = 0.222), or functionality (p = 0.254) between the four groups. A major limitation of this pilot study was the limited number of study participants in each group. CONCLUSION: This pilot study suggests that a large-scale clinical study with an adequate sample size would be warranted to compare acupuncture and medication therapy for chronic pain management. TRIAL REGISTRATION NUMBER: NCT01678586 (ClinicalTrials.gov).

A randomized trial to assess the immediate impact of acupuncture on quantitative sensory testing, pain, and functional status.

In this randomized clinical trial, we examined whether the effect of true acupuncture can be differentiated from sham acupuncture (pain and functionality) by analyzing quantitative sensory testing (QST) profiles in chronic pain participants. We recruited 254 healthy or chronic back and neck pain participants. Healthy subjects were included to control for a possible effect of acupuncture on baseline QST changes. Study participants received 6 sessions (twice weekly) of true acupuncture, sham acupuncture, or no acupuncture treatment (routine care). Quantitative sensory testing profiles, pain scores, and functionality profile were obtained at baseline (visit 1) and after 3 (visit 4) or 6 sessions (visit 7). A total of 204 participants were analyzed. We found no QST profile changes among 3 groups (P = 0.533 and P = 0.549, likelihood ratio tests) in either healthy or chronic pain participants. In chronic back and neck pain participants, true acupuncture reduced pain (visit 4: difference in mean [DIM] = -0.8, 95% confidence interval [CI]: -1.4 to -0.1, adjusted P = 0.168; visit 7: DIM = -1.0, 95% CI: -1.7 to -0.3, adjusted P = 0.021) and improved functional status including physical functioning (DIM = 14.21, 95% CI: 5.84-22.58, adjusted P = 0.003) and energy/fatigue (DIM = 12.28, 95% CI: 3.46-21.11, adjusted P = 0.021) as compared to routine care. Our results indicate that QST was not helpful to differentiate between true acupuncture and sham acupuncture (primary outcome) in this study, although true acupuncture reduced pain and improved functionality (secondary outcomes) when compared with routine care.

Gut microbiota is critical for the induction of chemotherapy-induced pain.

Chemotherapy-induced pain is a dose-limiting condition that affects 30% of patients undergoing chemotherapy. We found that gut microbiota promotes the development of chemotherapy-induced mechanical hyperalgesia. Oxaliplatin-induced mechanical hyperalgesia was reduced in germ-free mice and in mice pretreated with antibiotics. Restoring the microbiota of germ-free mice abrogated this protection. These effects appear to be mediated, in part, by TLR4 expressed on hematopoietic cells, including macrophages.

Nortriptyline Enhances Morphine-Conditioned Place Preference in Neuropathic Rats: Role of the Central Noradrenergic System.

BACKGROUND: Combination drug therapy is commonly used to treat chronic pain conditions such as neuropathic pain, and antidepressant is often used together with opioid analgesics. While rewarding is an intrinsic property of opioid analgesics, it is unknown whether the use of an antidepressant would influence opioid reward, which may contribute to opioid addiction. In this study, we examined whether nortriptyline (a tricyclic antidepressant and a first-line medication for neuropathic pain) would enhance the morphine rewarding property in both naive and chronic constriction sciatic nerve injury (CCI) rats. METHODS: The rewarding effect of these drugs was assessed using conditioned place preference (CPP). The real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay analysis were used to investigate the function of central noradrenergic system. RESULTS: In naive rats, coadministration of nortriptyline with morphine did not change the acquisition of morphine-induced CPP. However, nortriptyline enhanced the acquisition, delayed the extinction, and augmented the reinstatement of morphine-induced CPP in CCI rats. In CCI rats treated with both nortriptyline and morphine, the expression of α2A-adrenergic receptors, norepinephrine transporter, and tyrosine hydroxylase was markedly decreased in the locus coeruleus, whereas the norepinephrine concentration in the nucleus accumbens was remarkably increased. CONCLUSIONS: These results demonstrate that nortriptyline enhanced morphine reward when both drugs were used to treat neuropathic pain in rats and that this behavioral phenotype is likely to be mediated by upregulation of the central noradrenergic system. These findings may have implications in opioid therapy commonly used for chronic pain management.

A leptin-mediated central mechanism in analgesia-enhanced opioid reward in rats.

Opioid analgesics are commonly used in chronic pain management despite a potential risk of rewarding. However, it remains unclear whether opioid analgesia would enhance the opioid rewarding effect thereby contributing to opioid rewarding. Utilizing a rat paradigm of conditioned place preference (CPP) combined with ankle monoarthritis as a condition of persistent nociception, we showed that analgesia induced by either morphine or the nonsteroid anti-inflammatory drug ibuprofen increased CPP scores in arthritic rats, suggesting that analgesia itself had a rewarding effect. However, arthritic rats exhibited a significantly higher CPP score in response to morphine than ibuprofen. Thus, the rewarding effect of morphine was enhanced in the presence of persistent nociception, producing a phenomenon of analgesia-enhanced opioid reward. At the cellular level, administration of morphine activated a cascade of leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens (NAc), while administration of ibuprofen decreased glial activation with no effect on leptin expression in the NAc. Furthermore, the morphine rewarding effect was blocked in leptin deficient ob/ob mice or by neutralizing leptin or interleukin-1ß in the NAc without diminishing morphine analgesia. The data indicate that systemic opioid can activate a leptin-mediated central mechanism in the NAc that led to the enhanced opioid rewarding effect. These findings provide evidence for an interaction between opioid analgesia and opioid rewarding, which may have implications in clinical opioid dose escalation in chronic pain management.

Spinal expression of Hippo signaling components YAP and TAZ following peripheral nerve injury in rats.

Previous studies have shown that the morphology and number of cells in the spinal cord dorsal horn could change following peripheral nerve injury and that the Hippo signaling pathway plays an important role in cell growth, proliferation, apoptosis, and dendritic remolding. In the present study, we examined whether the expression of YAP and TAZ, two critical components regulated by Hippo signaling, in the spinal cord dorsal horn would be altered by chronic constriction sciatic nerve injury (CCI). We found that (1) YAP was mainly expressed on CGRP- and IB4-immunoreactive primary afferent nerve terminals without noticeable expression on glial cells, whereas TAZ was mainly expressed on spinal cord second order neurons as well as microglia; (2) upregulation of YAP and TAZ expression followed two distinct temporal patterns after CCI, such that the highest expression of YAP and TAZ was on day 14 and day 1 after CCI, respectively; (3) there were also unique topographic patterns of YAP and TAZ distribution in the spinal cord dorsal horn consistent with their distinctive association with primary afferents and second order neurons; (4) changes in the YAP expression were selectively induced by CCI but not CFA-induced hindpaw inflammation; and (5) the number of nuclear profiles of TAZ expression was significantly increased after CCI, indicating translocation of TAZ from the cytoplasma to nucleus. These findings indicate that peripheral nerve injury induced time-dependent and region-specific changes in the spinal YAP and TAZ expression. A role for Hippo signaling in synaptic and structural plasticity is discussed in relation to the cellular mechanism of neuropathic pain.

Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression.

Pain and depression are frequently comorbid disorders, but the mechanism underlying this association is unknown. Here, we report that brain indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting enzyme in tryptophan metabolism, plays a key role in this comorbidity. We found that chronic pain in rats induced depressive behavior and IDO1 upregulation in the bilateral hippocampus. Upregulation of IDO1 resulted in the increased kynurenine/tryptophan ratio and decreased serotonin/tryptophan ratio in the bilateral hippocampus. We observed elevated plasma IDO activity in patients with both pain and depression, as well as in rats with anhedonia induced by chronic social stress. Intra-hippocampal administration of IL-6 in rats, in addition to in vitro experiments, demonstrated that IL-6 induces IDO1 expression through the JAK/STAT pathway. Further, either Ido1 gene knockout or pharmacological inhibition of hippocampal IDO1 activity attenuated both nociceptive and depressive behavior. These results reveal an IDO1-mediated regulatory mechanism underlying the comorbidity of pain and depression and suggest a new strategy for the concurrent treatment of both conditions via modulation of brain IDO1 activity.

Leptin enhances NMDA-induced spinal excitation in rats: A functional link between adipocytokine and neuropathic pain.

Recent studies have shown that leptin (an adipocytokine) played an important role in nociceptive behavior induced by nerve injury, but the cellular mechanism of this action remains unclear. Using the whole-cell patch-clamp recording from rat's spinal cord slices, we showed that superfusion of leptin onto spinal cord slices dose-dependently enhanced N-methyl-d-aspartate (NMDA) receptor-mediated currents in spinal cord lamina II neurons. At the cellular level, the effect of leptin on spinal NMDA-induced currents was mediated through the leptin receptor and the JAK2/STAT3 (but not PI3K or MAPK) pathway, as the leptin effect was abolished in leptin receptor-deficient (db/db) mice and inhibited by a JAK/STAT inhibitor. Moreover, we demonstrated in naïve rats that a single intrathecal administration of leptin enhanced spontaneous biting, scratching, and licking behavior induced by intrathecal NMDA and that repeated intrathecal administration of leptin elicited thermal hyperalgesia and mechanical allodynia, which was attenuated by the noncompetitive NMDA receptor antagonist MK-801. Intrathecal leptin also upregulated the expression of NMDA receptors and pSTAT3 within the rat's spinal cord dorsal horn, and intrathecal MK-801 attenuated this leptin effect as well. Our data demonstrate a relationship between leptin and NMDA receptor-mediated spinal neuronal excitation and its functional role in nociceptive behavior. Since leptin contributes to nociceptive behavior induced by nerve injury, the present findings suggest an important cellular link between the leptin's spinal effect and the NMDA receptor-mediated cellular mechanism of neuropathic pain. A functional link is demonstrated between leptin, an adipocytokine, and the cellular mechanisms of neuropathic pain via enhancement of function and expression of spinal N-methyl-d-aspartate receptors.

Anti-morphine antibody contributes to the development of morphine tolerance in rats.

Previous studies have shown that tolerance to the antinociceptive effect of morphine develops after a prolonged exposure, but its mechanisms remain unclear. In the present study, we examined whether anti-morphine antibody produced by chronic morphine exposure would contribute to the development of morphine antinociceptive tolerance in rats. Our results showed that anti-morphine antibody was present in rats rendered tolerance to antinociception after intrathecal morphine exposure for seven consecutive days. Superfusion of anti-morphine antibody onto spinal cord slice dose-dependently produced an inward excitatory current in spinal cord dorsal horn neurons using whole-cell patch-clamp recording, which surpassed morphine-induced outward inhibiting current. Co-administration of morphine with a monoclonal antibody (2.4G(2)) against Fc receptors for seven days significantly attenuated the production of anti-morphine antibody as well as the behavioral manifestation of morphine tolerance in same rats. These results indicate that anti-morphine antibody produced by morphine exposure may contribute to the development of morphine tolerance possibly through counteracting the inhibitory morphine effect on spinal cord dorsal horn neurons.

Animal models of acute surgical pain.

Animal models of tissue injury have been used to investigate the mechanisms of pain. Here, we describe a variety of animal models that have been used to mimic acute surgical pain in human subjects, which include the plantar, tail, and gastrocnemius incision models. We also provide discussion on animal models of laparotomy, thoracotomy, visceral pain, and bone injury. Preclinical studies using these models have provided insights into the mechanisms and causes of acute surgical pain as well as the treatment options to control postsurgical pain.