TsNTxP, a non-toxic protein from Tityus serrulatus scorpion venom, induces antinociceptive effects by suppressing glutamate release in mice.

Neuropathic pain is a common type of chronic pain caused by trauma or chemotherapy. However, this type of pain is undertreated. TsNTxP is a non-toxic protein isolated from the venom of the scorpion Tityus serrulatus, and it is structurally similar to neurotoxins that interact with voltage-gated sodium channels. However, the antinociceptive properties of this protein have not been characterized. The purpose of this study was to investigate the antinociceptive effects of TsNTxP in acute and neuropathic pain models. Male and female Swiss mice (25-30 g) were exposed to different models of acute pain (tail-flick test and nociception caused by capsaicin intraplantar injection) or neuropathic pain (chronic pain syndrome induced by paclitaxel or chronic constriction injury of the sciatic nerve). Hypersensitivity to mechanical or cold stimuli were evaluated in the models of neuropathic pain. The ability of TsNTxP to alter the release of glutamate in mouse spinal cord synaptosomes was also evaluated. The results showed that TsNTxP exerted antinociceptive effects in the tail-flick test to a thermal stimulus and in the intraplantar capsaicin administration model. Furthermore, TsNTxP was non-toxic and exerted antiallodynic effects in neuropathic pain models induced by chronic constriction injury of the sciatic nerve and administration of paclitaxel. TsNTxP reduced glutamate release from mouse spinal cord synaptosomes following stimulation with potassium chloride (KCl) or capsaicin. Thus, this T. serrulatus protein may be a promising non-toxic drug for the treatment of neuropathic pain.

Diosmetin as a novel transient receptor potential vanilloid 1 antagonist with antinociceptive activity in mice.

Diosmetin is an O­methylated flavone found naturally in citrus fruit, and it was identified in Amphilophium crucigerum (L.), a plant popularly used as an analgesic. This compound had different pharmacological effects and presented a chemical structure like the flavonoid eriodyctiol that exhibited antinociceptive effects by TRPV1 antagonism. However, the possible antinociceptive effect of this compound was not well documented. Thus, the goal of the present study was to evaluate the antinociceptive effect of diosmetin and its mechanism of action. The diosmetin effect on different pain models and its possible adverse effects were assessed on adult Swiss male mice (25-30 g). Mice spinal cord samples were used on calcium influx and binding assays using TRPV1 agonists. First, it was observed that the diosmetin reduced calcium influx mediated by capsaicin in synaptosomes and displace the specific binding to [3H]-resiniferatoxin in membrane fractions from the spinal cord of mice. Diosmetin (0.15 to 1.5 mg/kg, intragastric, i.g.) presented antinociceptive and antiedematogenic effect in the capsaicin intraplantar test and induced antinociception in a noxious heat test (48 °C). Also, treatment with diosmetin reduced mechanical and heat hypersensitivity observed in a model of inflammatory or neuropathic pain. Acute diosmetin administration in mice did not induce locomotor or body temperature changes, or cause liver enzyme abnormalities or alter renal function. Moreover, there were no observed changes in gastrointestinal transit or induction of ulcerogenic activity after diosmetin administration. In conclusion, our results support the antinociceptive properties of diosmetin which seems to occur via TRPV1 antagonist in mice.

Topical treatment with a transient receptor potential ankyrin 1 (TRPA1) antagonist reduced nociception and inflammation in a thermal lesion model in rats.

Thermal injury promotes tissue inflammation and pain, which is difficult to control. Different peripheral mechanisms seem to be involved in burn pain, such as free radical-induced damage, but further study is still needed to understand how oxidant substances induced nociceptor sensitization. The transient receptor potential ankyrin 1 (TRPA1) is an ion channel activated by oxidants substances, and it could be sensitized after tissue inflammation. This study evaluated the TRPA1 involvement in nociception and inflammation produced by a thermal injury model. Male Wistar rats were used. The concentration of the TRPA1 antagonist (HC-030031, 0.05%) on base cream was chosen using allyl isothiocyanate intraplantar test. Then, the base cream containing HC-030031 was tested on the thermal injury model (induced by warm water immersion of hind paw, under anesthesia), and silver sulfadiazine (1%) was used as a positive control. Cream treatments on the hind paw were done daily (200 mg/paw) for 6 days after thermal injury. Also, nociception (static and dynamic mechanical allodynia, heat allodynia, and spontaneous pain) or edema were evaluated. On day 6, inflammatory and oxidative parameters were assessed. The base cream containing HC-030031 produced antinociceptive and anti-inflammatory effects (reduced the edema and inflammatory cells infiltration) and decreased the levels of hydrogen peroxide, or superoxide dismutase and NADPH oxidase activities after thermal injury. Thus, this study showed the involvement of the TRPA1 receptor in the nociception and inflammation caused by thermal injury and suggested that TRPA1 antagonists might be useful as novel treatments for pain and inflammation by topical application.

The spider toxin Phα1ß recombinant possesses strong analgesic activity.

The native Phα1ß - a Voltage-Gated Calcium Channel (VGCC) blocker - and its Recombinant Version - were both tested in rodent pain models with an intraplantar injections of capsaicin or formalin, a chronic constriction injury, and melanoma cancer related pain. The formalin nociceptive behaviour in the neurogenic phase was not affected by the toxin pre-treatments, while in the inflammatory phase, Phα1ß and the Recombinant form caused a significant reduction. The nociception that was triggered by capsaicin, an agonist of the TRPV1 vanilloid receptor, was totally blocked by 100 pmol/site, i.t. of Phα1ß or the recombinant version. For the neuropathic pain that was induced by a chronic constriction injury of the sciatic nerve, Phα1ß and its Recombinant reduced the allodynia that was induced by the CCI procedure in the rats and the hypersensitivity lasted for 4 h. Fourteen days after the inoculation of the B16-F10 melanoma cells in the mice, a marked hyperalgesia was induced in the melanoma cancer pain model. Phα1ß and the Recombinant form reduced the hyperalgesia with a full reversion at 100 pmol/site i.t. The inhibitory effects of the nociception that was induced by native Phα1ß and the Recombinant in the studied pain models were not statistically different and they developed with no side effects.