Paroxetine effects on morphine analgesic tolerance in rats.

OBJECTIVES: To alleviate different pain intensities, morphine administration has been extensively used. However, prolonged administration of morphine leads to a progressive decline of its analgesic effect which limits their overall utility. Morphine tolerance is considered as a challenging issue for the treatment of both acute and chronic pain. We conducted this study in rats to investigate the effect of paroxetine on morphine tolerance when used preemptively or after morphine tolerance had developed. METHODS: Male Wistar rats (weight 250-300 g, n=10) were used to evaluate the effects of paroxetine on tolerance to morphine. In order to induce tolerance, daily intraperitoneal injection of morphine (7 mg/kg) was done. After tolerance induction, a group of animals received intraperitoneal injection of 10 mg/kg paroxetine 30 min prior to each morphine dose. In another trial, to investigate the potential of paroxetine to prevent tolerance to morphine, animals were pretreated with 10 mg/kg paroxetine 30 min before morphine administration. In the control groups, 10 mL/kg of saline was injected. The behavioral test (tail-flick test) was done for all groups. RESULTS: Our data showed that paroxetine significantly reversed tolerance to morphine when used after tolerance induction (p<0.001). However, administration of paroxetine before occurrence of tolerance had no effect. CONCLUSIONS: We conclude that paroxetine could decrease tolerance to morphine when used after the occurrence of morphine tolerance, while it was not able to prevent morphine tolerance when administered preemptively. ETHICAL COMMITTEE NUMBER: IRIB.SBMU.MSP.REC.1394.098.

The effect of microglial inhibition on the expression of BDNF, KCC2, and GABAA receptor before and after the establishment of CCI-induced neuropathic pain model.

Damage to the peripheral or central nervous system results in neuropathic pain. Based on a complicated mechanism, neuropathic pain has no efficient treatment so far. It has been well-known that the expression of some proteins (BDNF, KCC2, GABA-A) during neuropathic pain changes. Microglial cell activation is considered as a trigger to alter the expression of these proteins. In the current study, the effect of minocycline as a potent microglial activation inhibitor on the gene and protein expression of these neuropathic pain mediators was investigated. This experiment was done in two paradigms, preinjury and postinjury administration of minocycline. In each paradigm, male Wistar rats (weight 150-200 g, n = 6) were allocated to sham, control, and drug groups. Minocycline (30 mg/kg, i.p.) was injected 1 h before or at day seven after nerve injury and continued till day 14 in the preemptive or postinjury part of the study, respectively. After the last injection, the animals were decapitated and the lumbar part of the spinal cord was isolated to assess the expression of genes and proteins of interest. In the preventive study, minocycline increased the expression of KCC2 and GABA-A/γ2 proteins and decreased BDNF expression. On the other hand, the target gene expression and protein expression were not changed when minocycline was administered after nerve injury. It seems that minocycline was able to change the expression of proteins of interest merely when used before nerve damage.

Purinergic receptor ligands: the cytokine storm attenuators, potential therapeutic agents for the treatment of COVID-19.

The coronavirus disease-19 (COVID-19), at first, was reported in Wuhan, China, and then rapidly became pandemic throughout the world. Cytokine storm syndrome (CSS) in COVID-19 patients is associated with high levels of cytokines and chemokines that cause multiple organ failure, systemic inflammation, and hemodynamic instabilities. Acute respiratory distress syndrome (ARDS), a common complication of COVID-19, is a consequence of cytokine storm. In this regard, several drugs have been being investigated to suppress this inflammatory condition. Purinergic signaling receptors comprising of P1 adenosine and P2 purinoceptors play a critical role in inflammation. Therefore, activation or inhibition of some subtypes of these kinds of receptors is most likely to be beneficial to attenuate cytokine storm. This article summarizes suggested therapeutic drugs with potential anti-inflammatory effects through purinergic receptors.

Effect of Paroxetine on the Neuropathic Pain: A Molecular Study.

Background: Neuropathic pain, due to peripheral nerve damage, has influenced millions of people living all over the world. It has been shown that paroxetine can relieve neuropathic pain. Recently, the role of certain proteins like brain-derived neurotrophic factor (BDNF), GABAA receptor, and K+-Cl- cotransporter 2 (KCC2) transporter in the occurrence of neuropathic pain has been documented. In the current study, the expression of these proteins affected by paroxetine was evaluated. Methods: Male Wistar rats were allocated into two main groups of pre- and post-injury. Rats in each main group received paroxetine before nerve injury and at day seven after nerve damage till day 14, respectively. The lumbar spinal cord of animals was extracted to assess the expression of target genes and proteins. Results: In the preventive study, paroxetine decreased BDNF and increased KCC2 and GABAA gene and protein expression, while in the post-injury paradigm, it decreased BDNF and increased KCC2 genes and protein expression. In this regard, an increase in the protein expression of GABAA was observed. Conclusion: It seems that paroxetine with a change in the expression of three significant proteins involved in neuropathic pain could attenuate this type of chronic pain.

How Nitric Oxide Increases in Diabetic Morphine Tolerated Male Rats.

Neuropathic pain is a complication of inflammation, infection or some diseases such as diabetes. Opioids are used as a salvage therapy for neuropathic pain but tolerance restricts their use. In our previous study, we have observed an increase of Nitric Oxide in diabetes and in morphine tolerance. This study was performed to clarify the role of inducible nitric oxide synthase, iNOS, and cationic amino acid transporter-2, CAT-2, in these conditions. Thus male rats were divided into four groups: control, diabetic, morphine tolerated, and diabetic morphine tolerated. For evaluating tolerance Hot-Plate test was achieved. Molecular study was performed by real time PCR and Western blotting techniques to compare gene and protein expressions. Our findings showed that in diabetic animals, morphine tolerance occurred prior to non-diabetic rats. In molecular study, the expression of iNOS was increased in the spinal cord whereas the CAT-2 did not change in diabetic morphine tolerated rats. It seems that the nitric oxide elevation in diabetic morphine tolerated state is mostly due to the increase of iNOS in male rats.

Carbamazepine effects on pain management and serum IL-6, IL-10 evaluation in addicted patients undergoing surgery.

Postoperative pain control remains an important issue in the field of surgery. Assessing and managing patients with acute pain who are addicted to opioids are often challenging. It has been shown that, addicted patients are less tolerant to pain. There is limited evidence to guide the management of acute pain in these patients. Here we studied the effect of preemptive use of carbamazepine on pain behavior and serum IL-6, IL-10 levels in the addicted patients. 90 male patients (25-45 years, BMI 20-27), were divided into 3 group of 30 patients: 1- control, 2- addicted, 3- addicted patients receiving carbamazepine 400mg before surgery. The visual analog pain scale and serum levels of IL-6 and IL-10 were evaluated at time 0 (before surgery), 1 and 12h postoperatively. Compared with control and carbamazepine groups, addicted patients exhibited exaggerated pain behavior before and after surgery, however, postoperatively, a significant increase in pain behavior was seen in control compared to carbamazepine group. A decrease in serum IL-10 and an increase in IL-6 concentrations were observed in addicted patients. In the morphine abuser, a decrease in pain threshold, an increase in IL-6 and a decrease in IL-10 levels were evident compared with non-abuser subjects. Addition of carbamazepine improved pain sensation and serum IL-6 levels and a reduction in serum IL-10 level in control patients was paralleled to their recovery. It seems that, preemptive use of low dose of carbamazepine can improve postoperative pain and cytokine activities in the addicted patients.

Paradoxical effect of minocycline on established neuropathic pain in rat.

Neuropathic pain occurs after peripheral nerve damage, inflammation or infection. In this situation, microglial cells become activated and play a key role in producing pain. Minocycline (microglia inhibitor), was reported to reduce pain when used preventively. However, it seems that, when used after nerve injury, results in its pain reducing effects are different. In this regard, to assess the pain reducing differences of minocycline, neuropathic pain was induced by the ligation of the sciatic nerve in the rat which is recognized as chronic constriction injury (CCI) and minocycline was administered before and after sciatic nerve injury. Wistar male rats (200-250 g, n=6) were used in these experiments. Rats were distributed in various groups: vehicle-treated CCI (control), sham-operated and minocycline-treated CCI groups. In the first part of the experiment (pre-injury study), minocycline (10, 20, 30 and 40 mg/kg,) was injected one hour before surgery and then daily for two weeks. In the second part (post injury study), minocycline was administered: 1: at day one after nerve damage once a day to day 14, 2: at day seven after surgery and continued daily until day 14. Analgesimeter for thermal hyperalgesia and von Frey hairs for mechanical allodynia were used to evaluate pain behavior. Thermal hyperalgesia and mechanical allodynia were attenuated significantly, when minocycline used before surgery, while it was not able to reduce pain behavior administered after surgery. It seems that, in spite of what some previous studies have reported, here, minocycline is not able to attenuate established neuropathic pain.

Paroxetine attenuates the development and existing pain in a rat model of neurophatic pain.

BACKGROUND: P2X4 receptor (P2X4R), a purinoceptor expressed in activated spinal microglia, plays a key role in the pathogenesis of neuropathic pain. Spinal nerve injury induces up-regulation of P2X4R on activated microglia in the spinal cord, and blockade of this receptor can reduce neuropathic pain. The present study was undertaken to determine whether paroxetine, an inhibitor of P2X4R, could attenuate allodynia and hyperalgesia in chronic constriction injury (CCI) model of neuropathic pain when used preemptively or after the sciatic nerve injury. METHODS: Male Wistar rats (150-200 g, n = 6) were divided into 3 different groups: 1- CCI vehicle-treated group, 2- Sham group, and 3- CCI paroxetine-treated group. Paroxetine (10 mg/kg, i.p.) was administered 1 h before surgery and continued daily until day 14. In other part of the study, paroxetine (10 mg/kg, i.p.) was administered at day 7 post injury and continued daily until day 14. von Frey filaments for mechanical allodynia and analgesia meter for thermal hyperalgesia were used to assay pain behavior. RESULTS: In a preventive paradigm, paroxetine significantly attenuated both mechanical allodynia and thermal hyperalgesia (P<0.001). A significant decrease in pain behavior was seen with paroxetine on existing allodynia (P<0.001) and hyperalgesia (P<0.01) when initiated at day 7 post injury. CONCLUSION: It seems that paroxetine can attenuate pain behavior when administered before and also after sciatic nerve injury in CCI model of neuropathic pain.