Diabetic neuropathy is a common complication of both type 1 and type 2 diabetes, which affects over 90% of the diabetic patients. Although pain is one of the main symptoms of diabetic neuropathy, its pathophysiological mechanisms are not yet fully known. It is widely accepted that the toxic effects of hyperglycemia play an important role in the development of this complication, but several other hypotheses have been postulated. The management of diabetic neuropathic pain consists basically in excluding other causes of painful peripheral neuropathy, improving glycemic control as a prophylactic therapy and using medications to alleviate pain. First line drugs for pain relief include anticonvulsants, such as pregabalin and gabapentin and antidepressants, especially those that act to inhibit the reuptake of serotonin and noradrenaline. In addition, there is experimental and clinical evidence that opioids can be helpful in pain control, mainly if associated with first line drugs. Other agents, including for topical application, such as capsaicin cream and lidocaine patches, have also been proposed to be useful as adjuvants in the control of diabetic neuropathic pain, but the clinical evidence is insufficient to support their use. In conclusion, a better understanding of the mechanisms underlying diabetic neuropathic pain will contribute to the search of new therapies, but also to the improvement of the guidelines to optimize pain control with the drugs currently available.

Thyme (Thymus vulgaris L., Lamiaceae) is an aromatic and medicinal plant that has been used in folk medicine, phytopharmaceutical preparations, food preservatives, and as an aromatic ingredient. The effect of Thymus vulgaris essential oil (TEO) and its isolated constituents thymol and cavacrol (CVL) were studied in the following experimental models: ear edema, carrageenan-induced pleurisy, and chemotaxis in vitro. In the pleurisy model, TEO, CVL, and thymol significantly inhibited inflammatory edema. However, only TEO and CVL inhibited leukocyte migration. In the in vitro chemotaxis experiment, CVL inhibited leukocyte migration, whereas thymol exerted a potent chemoattractant effect. In the ear edema model, CVL (10 mg/ear), applied topically, reduced edema formation, exerting a topical anti-inflammatory effect. Thymol did not reduce edema formation but rather presented an irritative response, probably dependent on histamine and prostanoid release. Our data suggest that the antiinflammatory effects of TEO and CVL are attributable to the inhibition of inflammatory edema and leukocyte migration.

1 The eect of IL-1ra on response to intraplantar (i.pl.) injection of LPS, carrageenin, bradykinin, TNFa, IL-1b, IL-8, PGE 2 and dopamine was investigated in a model of mechanical hyperalgesia in rats. 2 IL-1ra inhibited hyperalgesic response to LPS, carrageenin, bradykinin, TNFa, and IL-1b, but not responses to IL-8, PGE 2 and dopamine. 3 A sheep anti-rat IL-1ra serum potentiated response to LPS, carrageenin, bradykinin, TNFa and IL-1b but not IL-8. 4 Carrageenin and LPS stimulated and production of immunoreactive TNFa, IL-1b and IL-1ra in the skin of injected paws. 5 The inhibition by IL-1ra of the hyperalgesic response to carrageenin was not aected by antibodies neutralizing IL-4 and IL-10. 6 In mice, IL-1ra inhibited the nociceptive response to i.p. injection of acetic acid. 7 These data suggest that IL-1ra, released at sites of in¯ammation, limits in¯ammatory hyperalgesia. This eect is independent of (IL-1ra-induced) IL-4 and IL-10 and appears to be the result of antagonism by IL-1ra of IL-1b-stimulated eicosanoid production.

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1 The eects of BK agonists and antagonists, and other hyperalgesic/antihyperalgesic drugs were measured (3 h after injection of hyperalgesic drugs) in a model of mechanical hyperalgesia (the endpoint of which was indicated by a brief apnoea, the retraction of the head and forepaws, and muscular tremor). 2 DALBK inhibited responses to carrageenin, bradykinin, DABK, and kallidin. 3 Responses to kallidin and DABK were inhibited by indomethacin or atenolol and abolished by the combination of indomethacin+atenolol. 4 DALBK or HOE 140, given 30 min before, but not 2 h after, carrageenin, BK, DABK and kallidin reduced hyperalgesic responses to these agents. 5 A small dose of DABK+a small dose of BK evoked a response similar to the response to a much larger dose of DABK or BK, given alone. 6 Responses to BK were antagonized by HOE 140 whereas DALBK antagonized only responses to larger doses of BK. The combination of a small dose of DALBK with a small dose of HOE 140 abolished the response to BK. 7 The hyperalgesic response to LPS (1 mg) was inhibited by DALBK or HOE 140 and abolished by DALBK+HOE 140. The hyperalgesic response to LPS (5 mg) was not antagonized by DALBK+HOE 140. 8 These data suggest: (a) a predominant role for B 2 receptors in mediating hyperalgesic responses to BK and to drugs that stimulate BK release, and (b) activation of the hyperalgesic cytokine cascade independently of both B 1 and B 2 receptors if the hyperalgesic stimulus is of sucient magnitude.