Tetracyclines and pain

Abstract

Tetracyclines are natural or semi-synthetic bacteriostatic agents which have been used since late 1940s against a wide range of gram-positive and gram-negative bacteria and atypical organisms such as chlamydia, mycoplasmas, rickettsia, and protozoan parasites. After the discovery of the first tetracyclines, a second generation of compounds was sought in order to improve water solubility for parenteral administration or to enhance bioavailability after oral administration. This approach resulted in the development of doxycycline and minocycline in the 1970s. Doxycycline was included in the World Health Organization Model List of Essential Medicines either as antibacterial or to prevent malaria or to treat patients with this disease. Additional development led to the third generation of tetracyclines, being tigecycline the only medicine of this class to date. Besides antibacterial activities, the anti-inflammatory, antihypernociceptive and neuroprotective activities of tetracyclines began to be widely studied in the late 1990s. Indeed, there has been an increasing interest in investigating the effects induced by minocycline as this liposoluble derivative is known to cross the blood-brain barrier to the greatest extent. Minocycline induces antihypernociceptive effects in a wide range of animal models of nociceptive, inflammatory and neuropathic pain. In this study, we discuss the antihypernociceptive activity of tetracyclines and summarise its underlying cellular and molecular mechanisms.

A minocycline derivative reduces nerve injury-induced allodynia, LPS-induced prostaglandin E2 microglial production and signaling via toll-like receptors 2 and 4

“…Therefore, we hypothesize that all these semi-synthetic tetracycline derivatives share similar anti-inflammatory activities that may underlie suppression of experimental pain. Among them, minocycline is the most widely studied [4]. It has been shown that minocycline, directly or indirectly, prevents activation of many enzymes involved in the synthesis of multiple inflammatory mediators in macrophage/microglia or neuronal cell lines or in cell-free assays.…”

“…It has been shown that minocycline, directly or indirectly, prevents activation of many enzymes involved in the synthesis of multiple inflammatory mediators in macrophage/microglia or neuronal cell lines or in cell-free assays. Among them, phospholipase A 2 , different protein kinase C isoforms, multiple mitogen-activated protein kinases, phosphatidylinositol 3-kinase/Akt, inducible nitric oxide synthase, cyclooxygenase (COX)-2, microsomal prostaglandin E synthase-1, 5-lipoxygenase and poly(ADP-ribose) polymerase-1 [4]. Besides anti-inflammatory actions on macrophages, microglia and neurons, direct actions on excitability of primary afferent neurons may also explain minocycline’s suppressive effects on experimental pain [4].…”

“…Tetracyclines induce pleiotropic effects unrelated to their broad antibacterial actions, including anti-inflammatory and neuroprotective effects [4]. Of the tetracyclines, minocycline has been the focus of the most studies given that it is the derivative which crosses the blood-brain barrier to the greatest extent [1].…”

“…Of the tetracyclines, minocycline has been the focus of the most studies given that it is the derivative which crosses the blood-brain barrier to the greatest extent [1]. Experimental studies have shown beneficial effects induced by minocycline in animal models of inflammatory and neuropathic pain [4]. …”

“…Further, deleting Ca 2+ chelation is important given its detrimental effects on developing bones and teeth, associated with teeth discoloration, gum dysplasia, dental hypoplasia or bone deformities [4]. …”