Evaluation of the effects of gabapentin on the physiologic and echocardiographic variables of healthy cats: a prospective, randomized and blinded study.

OBJECTIVES: The aim of this study was to evaluate, using echocardiography, the effects of oral administration of a single dose of gabapentin on the physiologic variables (heart rate [HR], respiratory rate [RR] and systolic blood pressure [SBP]) and systolic and diastolic cardiac function of healthy cats. METHODS: This was a prospective, randomized and blinded study with 40 healthy cats aged between 6 months and 2 years. The cats' health status was assessed on the first appointment (T1) when they underwent a physical examination, complete blood count, biochemical profile, assessment of physiologic variables and echocardiogram. The echocardiogram was used to measure the left ventricle's (LV) internal diameter during systole and diastole, isovolumic relaxation time, transmitral flow, E-wave deceleration time and HR. The cats were randomly divided into two groups: (1) a treatment group with 20 cats that received a single oral dose of gabapentin (100 mg/cat); and (2) a control group with 20 cats that received a single oral dose of placebo. All variables of the physiologic and echocardiographic variables were re-evaluated 1-3 weeks after T1 (T2), 90 mins after medication or placebo administration. RESULTS: There was no difference in the physiologic variables evaluated in both groups. The proportion of cats in the treatment group that had their ventricular filling waves fused on T1 but did not have them fused on T2 was significantly higher (45%) compared with cats in the control group (15%; P = 0.0384). CONCLUSIONS AND RELEVANCE: There was no difference between the groups in regard to SBP, HR, RR and echocardiographic variables. Gabapentin improved evaluation of diastolic function on echocardiogram because it reduced the fusion of ventricular filling waves during the evaluation of the diastolic function of the LV. Gabapentin did not cause adverse effects on the cardiovascular hemodynamics of young healthy cats.

Concomitant Antihyperalgesic and Antitumor Effects of Gabapentin in a Murine Cancer Pain Model.

Cancer pain may be the consequence of physical nerve compression by a growing tumor. We employed a murine model to study whether gabapentin was able to regulate tumor growth, in addition to controlling hyperalgesic symptoms. A fluorescent melanoma cell line (B16-BL6/Zs green) was inoculated into the proximity of the sciatic nerve in male C57BL/6 mice. The tumor gradually compressed the nerve, causing hypersensitivity. Tumor growth was characterized via in vivo imaging techniques. Every other day, gabapentin (100 mg/Kg) or saline was IP administered to each animal. In the therapeutic protocol, gabapentin was administered once the tumor had induced increased nociception. In the preventive protocol, gabapentin was administered before the appearance of the positive signs. Additionally, in vitro experiments were performed to determine gabapentin's effects on cell-line proliferation, the secretion of the chemokine CCL2, and calcium influx. In the therapeutically treated animals, baseline responses to noxious stimuli were recovered, and tumors were significantly reduced. Similarly, gabapentin reduced tumor growth during the preventive treatment, but a relapse was noticed when the administration stopped. Gabapentin also inhibited cell proliferation, the secretion of CCL2, and calcium influx. These results suggest that gabapentin might represent a multivalent strategy to control cancer-associated events in painful tumors.

Gabapentin Inhibits Multiple Steps in the Amyloid Beta Toxicity Cascade.

Oligomeric ß-amyloid peptide (Aß) is one of the main neurotoxic agents of Alzheimer's disease (AD). Oligomers associate to neuronal membranes, forming "pore-like" structures that cause intracellular calcium and neurotransmitter dyshomeostasis, leading to synaptic failure and death. Through molecular screening targeting the C terminal region of Aß, a region involved in the toxic properties of the peptide, we detected an FDA approved compound, gabapentin (GBP), with neuroprotective effects against Aß toxicity. At micromolar concentrations, GBP antagonized peptide aggregation over time and reduced the Aß absorbance plateau to 28% of control. In addition, GBP decreased Aß association to membranes by almost half, and the effects of Aß on intracellular calcium in hippocampal neurons were antagonized without causing effects on its own. Finally, we found that GBP was able to block the synaptotoxicity induced by Aß in hippocampal neurons, increasing post-synaptic currents from 1.7 ± 0.9 to 4.2 ± 0.7 fC and mean relative fluorescence intensity values of SV2, a synaptic protein, from 0.7 ± 0.09 to 1.00 ± 0.08. The results show that GBP can interfere with Aß-induced toxicity by blocking multiple steps, resulting in neuroprotection, which justifies advancing toward additional animal and human studies.

High dose gabapentin does not alter tumor growth in mice but reduces arginase activity and increases superoxide dismutase, IL-6 and MCP-1 levels in Ehrlich ascites.

OBJECTIVES: The purpose of this study was to evaluate the effect of gabapentin on Ehrlich tumor growth in Swiss mice, a highly aggressive and inflammatory tumor model. Mice were grouped into sets of 5 animals and treated from days 2 to 8 with gabapentin 30 mg/kg body weight (G30) or 100 mg/kg body weight (G100), or normal sterile saline (control). RESULTS: The mice were euthanized on day 10. Tumor growth, tumoricidal agents and inflammatory cytokines levels were assessed. At day 10, G30 and G100 mice gained weight, but there were no differences in tumor cell count or in ascites volume. In G100, there was a reduction in arginase and an increase in SOD activities. There was an increase in IL-6 and MCP-1 levels, especially in G100, but no alterations in TNF-α. There was no direct evidence of tumor induction by gabapentin. However, the findings suggest that its use modulates immune response to a more effector and less deleterious profile, with increase in activity of anti-oxidant enzymes and in cytokines that favor activation of macrophages, which could improve the general status of the tumor host.

The antihyperalgesic effect of docosahexaenoic acid in streptozotocin-induced neuropathic pain in the rat involves the opioidergic system.

Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid that has shown an antinociceptive effect in multiple pain models, such as inflammatory and neuropathic pain by chronic constriction injury in rats; however, its mechanism of action is still not well-understood. Reports suggest that DHA activates opioid signaling, but there is no information on this from a model of neuropathic pain. As a result, the aims of this study were (1) to determine the antihyperalgesic and antiallodynic effect of peripheral DHA administration, and (2) to evaluate the participation of the opioid receptors in the antihyperalgesic effect of DHA on streptozotocin-induced neuropathic pain in the rat. Female Wistar rats were injected with streptozotocin (50 mg/kg, i.p.) to induce hyperglycemia. The formalin, Hargreaves, and von Frey filaments tests were used to assess the nociceptive activity. Intraplantar administration of DHA (100-1000 µg/paw) or gabapentin (562-1778 µg/paw) decreased formalin-evoked hyperalgesia in diabetic rats, in a dose-dependent manner. Furthermore, DHA (562 µg/paw) and gabapentin (1000 µg/paw) reduced thermal hyperalgesia and allodynia. Local peripheral administration of naloxone (non-selective opioid receptor antagonist; 100 µg/paw), naltrindole (selective δ receptor antagonist; 1 µg/paw), and CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, µ receptor antagonist; 20 µg/paw) prevented formalin-evoked hyperalgesia in diabetic rats but not by GNTI (guanidinonaltrindole, κ receptor antagonist;1 µg/paw). It is suggested that peripheral DHA shows an antihyperalgesic effect in neuropathic pain in the rat. Furthermore, δ and µ receptors are involved in the antihyperalgesic peripheral effect of DHA in diabetic rats.

Interleukin-1beta in synergism gabapentin with tramadol in murine model of diabetic neuropathy.

Neuropathic pain is a complication of cancer and diabetes mellitus and the most commonly used drugs in the treatment of the diabetic neuropathic pain have only limited efficacy. The aim of this study was to evaluate the role of the biomarker interleukin-1beta (IL-1ß) in the pharmacological interaction of gabapentin with tramadol in a model of diabetic neuropathic pain. CF-1 male mice, pretreated with 200 mg/kg i.p. of streptozocin (STZ), were used and at day 3 and 7 were evaluated by the hot plate test and the spinal cord level of IL-1ß was determined. Antinociceptive interaction of the coadministration i.p. of gabapentin with tramadol, in basic of the fixed the ratio 1:1 of their ED50 values alone, was ascertained by isobolographic analysis. Tramadol was 1.13 times more potent than gabapentin in saline control mice, 1.40 times in STZ mice at 3 days and 1.28 times in STZ at 7 days. The interaction between gabapentin and tramadol was synergic, with an interaction index of 0.30 and 0.22 for mice pretreated with STZ at 3 and 7 days. The combination of gabapentin with tramadol reversed the increased concentration of IL-1ß induced by STZ in diabetic neuropathic mice. These findings could help clarify the mechanism of diabetic neuropathy.