Metformin effect in models of inflammation is associated with activation of ATP-dependent potassium channels and inhibition of tumor necrosis factor-α production.

Metformin is an oral hypoglycemic drug widely used in the management of type 2 diabetes mellitus. We have recently demonstrated that metformin exhibits activity in models of nociceptive and neuropathic pain. However, little is known about its effects in experimental models of inflammation and inflammatory pain. Thus, the present study aimed to evaluate the activity of metformin in experimental models of inflammation and inflammatory pain in mice, as well as the underlying mechanisms. Previous (1 h) per os (p.o.) administration of metformin (250, 500 or 1000 mg/kg) inhibited the mechanical allodynia and paw edema induced by intraplantar (i.pl.) injection of carrageenan (600 µg) and also the pleurisy induced by this stimulus (200 µg, intrapleural). In the model of mechanical allodynia and paw edema induced by carrageenan, metformin also exhibited activity when administered after (1 h) the inflammatory stimulus. Metformin (1000 mg/kg) reduced the production of tumor necrosis factor-α induced by i.pl. injection of carrageenan. Metformin antiallodynic effect was not affected by previous administration of naltrexone (5 or 10 mg/kg, intraperitoneal) or cyproheptadine (5 or 10 mg/kg, p.o). However, this effect was abolished by previous administration of glibenclamide (20 or 40 mg/kg, p.o). In conclusion, the results demonstrate the activity of metformin in models of inflammation and inflammatory pain. In addition, the results indicate that the activity of metformin may be mediated by activation of ATP-sensitive potassium channels and reduction of production of inflammatory mediators. Altogether, these results stimulate the conduction of studies aiming to evaluate whether metformin may be repositioned in the treatment of patients with painful and inflammatory disorders.

Clindamycin inhibits nociceptive response by reducing tumor necrosis factor-α and CXCL-1 production and activating opioidergic mechanisms.

Clindamycin, a bacteriostatic semisynthetic lincosamide, is useful in the management of infections caused by aerobic and anaerobic Gram-positive cocci, including bacteremic pneumonia, streptococcal toxic shock syndrome and sepsis. It has been recently demonstrated that clindamycin inhibits in vitro and in vivo inflammatory cytokine production. In the present study, we investigated the effects of clindamycin in acute and chronic models of pain and inflammation in mice and the underlying mechanisms. Intraperitoneal (i.p.) administration of clindamycin (400 mg/kg) increased the animal's latency to exhibit the nociceptive behavior induced by noxious heat (hot plate model). Intrathecal injection of clindamycin (2, 10 and 50 µg) also increased the animals' latency to exhibit the nociceptive behavior. Tactile hypersensitivity and paw edema induced by intraplantar (i.pl.) injection of carrageenan were attenuated by previous administration of clindamycin (200 and 400 mg/kg, i.p.). Clindamycin (100, 200 and 400 mg/kg, i.p.) also attenuated ongoing tactile hypersensitivity and paw edema induced by i.pl. injection of complete Freund's adjuvant (CFA). The antinociceptive activity of clindamycin (400 mg/kg, i.p.) in the hot plate model was attenuated by previous administration of naltrexone (5 and 10 mg/kg, i.p.), but not glibenclamide or AM251. CFA-induced production of TNF-α and CXCL-1 was reduced by clindamycin (400 mg/kg, i.p.). Concluding, clindamycin exhibits activities in acute and chronic models of pain and inflammation. These effects are associated with reduced production of TNF-α and CXCL-1 and activation of opioidergic mechanisms. Altogether, these results indicate that the clindamycin's immunomodulatory effects may contribute to a pharmacological potential beyond its antibiotic property.

Metformin antinociceptive effect in models of nociceptive and neuropathic pain is partially mediated by activation of opioidergic mechanisms.

Metformin, an AMP-activated protein kinase (AMPK) activator, is an oral hypoglycemic drug widely used to treat patients with type 2 diabetes. As AMPK plays a role in the nociceptive processing, investigating the effects induced by metformin in experimental models of pain is warranted. In the present study, we further evaluated the effects induced by metformin in models of nociceptive and neuropathic pain and investigated mechanisms that could mediate such effects. Metformin was administered per os (p.o.) in mice. Nociceptive response induced by heat (hot-plate) and mechanical allodynia induced by chronic constriction injury (CCI) were used as pain models. Naltrexone (intraperitoneal) and glibenclamide (p.o.) were used to investigate mechanisms mediating metformin effects. A single administration of metformin (500 or 1000 mg/kg) inhibited the nociceptive response in the hot-plate model. Single and repeated administration of metformin (250, 500 or 1000 mg/kg) inhibited the mechanical allodynia induced by CCI. Metformin (250, 500 or 1000 mg/kg) did not affect the time mice spent in the rota-rod apparatus. The activity of metformin (1000 mg/kg) in both pain models was attenuated by naltrexone (10 mg/kg), but not by glibenclamide. Concluding, metformin exhibited activity in models of nociceptive and neuropathic pain. In the model of neuropathic pain, preventive and therapeutic effects were observed. Activation of opioidergic pathways partially mediates metformin antinociceptive activity. Altogether, the results indicate that metformin should be further investigated aiming its repositioning in the treatment of patients with different painful conditions.

Nicorandil inhibits mechanical allodynia induced by paclitaxel by activating opioidergic and serotonergic mechanisms.

Recently, we demonstrated that nicorandil exhibits activities in models of inflammatory and nociceptive pain. In the present study, we extended this investigation by evaluating the effects of nicorandil in models of neuropathic pain induced by paclitaxel or nerve injury in mice. Four intraperitoneal (i.p.) injections of paclitaxel (2 mg/kg.day, cumulative dose 8 mg/kg) or chronic constriction injury (CCI) of the sciatic nerve induced a long lasting mechanical allodynia. Per os (p.o.) administration of two doses of nicorandil (50, 100 and 150 mg/kg) on the 14th day after the first paclitaxel injection attenuated the mechanical allodynia. Equimolar doses of nicotinamide (86.7 mg/kg, p.o.) or nicotinic acid (87.7 mg/kg, p.o.) were devoid of effect. Mechanical allodynia induced by CCI was also attenuated by p.o. administration of two doses of nicorandil (150 mg/kg) on the 14th day after nerve injury. Nicorandil (50, 100 and 150 mg/kg, p.o.) did not affect motor activity. The antinociceptive activity of nicorandil in the model of mechanical allodynia induced by paclitaxel was partially attenuated by naltrexone (5 and 10 mg/kg, i.p.) or cyproheptadine (5 and 10 mg/kg, i.p.), but not by glibenclamide (20 and 40 mg/kg, p.o.). Concluding, nicorandil exhibits activity in experimental models of neuropathic pain when mechanical allodynia is fully established. Activation of opioidergic and serotonergic pathways mediates the antinociceptive activity of nicorandil. It is unlikely that this activity requires biotransformation to nicotinamide or nicotinic acid. Nicorandil should be further evaluated aiming to identify a new alternative in the pharmacological management of neuropathic pain.

Opioid pathways activation mediates the activity of nicorandil in experimental models of nociceptive and inflammatory pain.

We have previously demonstrated that nicorandil inhibits the second phase of the nociceptive response induced by formaldehyde. In the present study, we evaluated the effects induced by nicorandil in other models of nociceptive and inflammatory pain in mice and also whether opioid pathways activation mediates its activity. As we have previously demonstrated, per os (p.o.) administration of nicorandil (50, 100 or 150mg/kg; -1h) inhibited the second phase of the nociceptive response induced by intraplantar (i.pl.) injection of formaldehyde. Nicorandil (50, 100 or 150mg/kg; p.o., -1h) also exhibited activity in models of inflammatory pain induced by i.pl. injection of carrageenan (300µg) and nociceptive pain induced by exposure to noxious heat (50°C). Intraperitoneal (i.p.) administration of the opioid antagonist naltrexone (1, 5 or 10mg/kg, -30min) attenuated or abolished the antinociceptive activity of nicorandil (100mg/kg, p.o.) in the three experimental pain models. In conclusion, we demonstrate that nicorandil exhibits activity in different models of nociceptive and inflammatory pain. The demonstration that the antinociceptive effect induced by nicorandil is markedly attenuated by an opioid antagonist provides solid information about an important mechanism mediating the activity of this antianginal drug. Altogether, our data suggest that the clinical pain relief induced by nicorandil in heart ischemic conditions may result from both vasodilation and intrinsic analgesic activity.