Ultrasound therapy reduces persistent post-thoracotomy tactile allodynia and spinal substance P expression in rats.

BACKGROUND: Therapeutic ultrasound (TU) alleviates nerve injury-associated pain, while the molecular mechanisms are less clear. This is an investigator-initiated experimental study to evaluate the mechanisms and effects of ultrasound on prolonged post-thoracotomy pain in a rodent model. METHODS: The rats were randomly separated into four groups (n=8 per group): sham-operation (sham; group 1), thoracotomy and rib retraction (TRR; group 2), and TRR procedure followed by TU (TRR+TU-3; group 3) or TU with the ultrasound power turned off (TRR+TU-0; group 4). TU was delivered daily, beginning on postoperative day 11 (POD 11) for the next 2 weeks. Mechanical sensitivity, subcutaneous tissue temperature, and spinal substance P and interleukin-1 beta (IL-1ß) were evaluated on PODs 11 and 23. RESULTS: Group 3, which received ultrasound treatment (3 MHz; 1.0 W/cm2) for 5 min each day, demonstrated higher mechanical withdrawal thresholds when compared with the group without ultrasound intervention (group 2) or sham ultrasound (group 4). Ultrasound treatment also inhibited the upregulation of spinal substance P and IL-1ß measured from spinal cord dorsal horns extract and increased subcutaneous temperature. CONCLUSIONS: The results of this study suggest an increase in mechanical withdrawal thresholds and subcutaneous temperature, as well as a downregulation of spinal substance P and IL-1ß, in the group which received ultrasound treatment. The regulation of spinal substance P and IL-1ß may mediate potential effects of this non-invasive treatment.

Adding Dopamine to Proxymetacaine or Oxybuprocaine Solutions Potentiates and Prolongs the Cutaneous Antinociception in Rats.

BACKGROUND: We evaluated the interaction of dopamine-proxymetacaine and dopamine- oxybuprocaine antinociception using isobolograms. METHODS: This experiment uses subcutaneous drug (proxymetacaine, oxybuprocaine, and dopamine) injections under the skin of the rat's back, thus simulating infiltration blocks. The dose-related antinociceptive curves of proxymetacaine and oxybuprocaine alone and in combination with dopamine were constructed, and then the antinociceptive interactions between the local anesthetic and dopamine were analyzed using isobolograms. RESULTS: Subcutaneous proxymetacaine, oxybuprocaine, and dopamine produced a sensory block to local skin pinpricks in a dose-dependent fashion. The rank order of potency was proxymetacaine (0.57 [0.52-0.63] µmol/kg) > oxybuprocaine (1.05 [0.96-1.15] µmol/kg) > dopamine (165 [154-177] µmol/kg; P < .01 for each comparison) based on the 50% effective dose values. On the equianesthetic basis (25% effective dose, 50% effective dose, and 75% effective dose), the nociceptive block duration of proxymetacaine or oxybuprocaine was shorter than that of dopamine (P < .01). Oxybuprocaine or proxymetacaine coinjected with dopamine elicited a synergistic antinociceptive effect and extended the duration of action. CONCLUSIONS: Oxybuprocaine and proxymetacaine had a higher potency and provoked a shorter duration of sensory block compared with dopamine. The use of dopamine increased the quality and duration of skin antinociception caused by oxybuprocaine and proxymetacaine.

Exercise Combined With Ultrasound Attenuates Neuropathic Pain in Rats Associated With Downregulation of IL-6 and TNF-α, but With Upregulation of IL-10.

BACKGROUND: Although there are several evidences that suggest efficacies of therapeutic ultrasound (TU) or treadmill exercise (TE) to alleviate nerve injury-associated pain, molecular mechanisms are less clear. We aimed to investigate the impact of TU and/or TE on neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve and their roles of proinflammatory and anti-inflammatory cytokines. METHODS: Rats were randomly divided into (n = 10 per group) sham operation (sham), CCI procedure followed by false application of TU (CCI + TU0), CCI procedure followed by false application of TU and TE (CCI + TU0 + TE), CCI, and CCI procedure followed by TU alone (CCI + TU), TE alone (CCI + TE), or both TU and TE (CCI + TU + TE) groups. TU and TE were administered daily, starting on postoperative day 8 (POD 8) for 3 weeks. Mechanical and thermal hypersensitivity, tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and IL-6 in the sciatic nerve were assessed on PODs 14 and 28. Data were analyzed by 1-way, 2-way, or 3-way analysis of variance of repeated measures or 1-way analysis of variance. RESULTS: After the interventions, there was statistical significance (all P ≤ .0001) between the groups for all outcome parameters, all in favor of the experimental group: 4.2 for mean mechanical withdrawal thresholds (95% confidence interval, 1.8-7.6) and 4.8 for mean thermal withdrawal latencies (95% confidence interval, 2.2-8.1). TU and/or TE provoked an increase in mechanical withdrawal thresholds and thermal withdrawal latencies in CCI rats. TU + TE was more effective to reverse pain hypersensitivity than having each treatment alone. On PODs 14 and 28, the CCI rats exhibited an upregulation of sciatic TNF-α and IL-6 expression, whereas TU or TE alone or TU + TE combination prevented the upregulation. TU and/or TE also showed the upregulation of less IL-10 expression in the sciatic nerve. CONCLUSIONS: We found that TU + TE is better than TU or TE alone for treating neuropathic pain. TU and/or TE for pain management may be straightly associated with less TNF-α and IL-6 expression and more IL-10 expression.

Intrathecal amantadine for prolonged spinal blockade of sensory and motor functions in rats.

We aimed to compare the hypothesized local anesthetic action of amantadine (1-adamantanamine) with that of the known local anesthetic mepivacaine. Motor, proprioceptive, and nociceptive functions were evaluated in rats after intrathecal administration. Amantadine elicited spinal anesthesia in a dose-related fashion and produced a better sensory-selective action over motor blockade (P < 0.01). On the 50% effective dose (ED50 ) basis, the rank of potency on spinal motor, proprioceptive, and nociceptive block was mepivacaine > amantadine (P < 0.01 for the differences). Amantadine (63.5 µmol/kg) and mepivacaine (7.1 µmol/kg) produced complete spinal block of motor function, proprioception, and nociception. On an equipotent basis (ED25 , ED50 , and ED75 ), the duration of amantadine was longer (P < 0.01) than that of mepivacaine on spinal motor, proprioceptive, and nociceptive block. Our preclinical data demonstrated that amantadine was less potent than mepivacaine at producing spinal anesthesia. The spinal block duration produced by amantadine was greater than that produced by mepivacaine. Both amantadine and mepivacaine produced a markedly nociceptive-specific blockade.

Chlorpheniramine produces spinal motor, proprioceptive and nociceptive blockades in rats.

This study aimed to assess the local anesthetic effects of chlorpheniramine in spinal anesthesia and is compared with mepivacaine, a widely-used local anesthetic. Spinal anesthesia with chlorpheniramine and mepivacaine was constructed in a dosage-dependent fashion after the rats were injected intrathecally. The spinal block effect of chlorpheniramine in motor function, nociception, and proprioception was compared to that of mepivacaine. We revealed that intrathecal chlorpheniramine and mepivacaine exhibited a dose-dependent spinal block of motor function, nociception, and proprioception. On the 50% effective dose (ED50) basis, the ranks of potencies in motor function, nociception, and proprioception were chlorpheniramine>mepivacaine (P<0.01 for the differences). On the equianesthetic basis (ED25, ED50, ED75), the duration of spinal anesthesia with chlorpheniramine was greater than that of mepivacaine (P<0.01 for the differences). Instead of mepivacaine, chlorpheniramine produced a greater duration of sensory blockade than the motor blockade. These preclinical data showed that chlorpheniramine has a better sensory-selective action over motor block to produce more potent and long-lasting spinal anesthesia than mepivacaine.

High frequency transcutaneous electrical nerve stimulation with diphenidol administration results in an additive antiallodynic effect in rats following chronic constriction injury.

The impact of coadministration of transcutaneous electrical nerve stimulation (TENS) and diphenidol is not well established. Here we estimated the effects of diphenidol in combination with TENS on mechanical allodynia and tumor necrosis factor-α (TNF-α) expression. Using an animal chronic constriction injury (CCI) model, the rat was estimated for evidence of mechanical sensitivity via von Frey hair stimulation and TNF-α expression in the sciatic nerve using the ELISA assay. High frequency (100Hz) TENS or intraperitoneal injection of diphenidol (2.0µmol/kg) was applied daily, starting on postoperative day 1 (POD1) and lasting for the next 13 days. We demonstrated that both high frequency TENS and diphenidol groups had an increase in mechanical withdrawal thresholds of 60%. Coadministration of high frequency TENS and diphenidol gives better results of paw withdrawal thresholds in comparison with high frequency TENS alone or diphenidol alone. Both diphenidol and coadministration of high frequency TENS with diphenidol groups showed a significant reduction of the TNF-α level compared with the CCI or HFS group (P<0.05) in the sciatic nerve on POD7, whereas the CCI or high frequency TENS group exhibited a higher TNF-α level than the sham group (P<0.05). Our resulting data revealed that diphenidol alone, high frequency TENS alone, and the combination produced a reduction of neuropathic allodynia. Both diphenidol and the combination of diphenidol with high frequency TENS inhibited TNF-α expression. A moderately effective dose of diphenidol appeared to have an additive effect with high frequency TENS. Therefore, multidisciplinary treatments could be considered for this kind of mechanical allodynia.