Corneal Toxicity of Xylazine and Clonidine, in Combination with Ketamine, in the Rat

Abstract

Purpose: To compare the corneal toxicity of xylazine (XYL)/ketamine (KET) with that of clonidine (CLO)/KET in the rat, in the presence or not of the α₂-adrenergic antagonist yohimbine (YOH). Methods: XYL (10 mg/kg) and CLO (0.15 mg/kg) were administered subcutaneously in the rat in combination with KET (50 mg/kg), in the presence or not of YOH (2 mg/kg). Results: The corneas immediately lost transparency and luster, but recovered within 120 min. By both light and electron microscopy, a marked stromal edema and alterations of all layers were observed. In addition, XYL/KET altered the permeability of the cornea as indicated by the augmented levels of ¹⁴C-indomethacin, topically administered 30 min after the anesthetic combination. Conclusions: The mechanism of the corneal toxicity of XYL and CLO in the rat is unclear but we speculate that: (a) proptosis and inhibition of normal blinking did not play a major role because topical application of hyaluronic acid did not protect against it; corneal decompensation, edema and opacification could be due to (b) osmotic or (c) mechanical endothelial stress: the first resulting from the sudden increase of the glucose concentration in the aqueous humor due to the well-known inhibition of insulin release by α₂-adrenergic agonists, and the second from the acute elevation of intraocular pressure caused by these α₂-adrenergic mydriatics in the rat; (d) addition, XYL and CLO could act by directly interacting with local α₂- or, possibly, α₁-adrenergic receptors, whose function is still not clear but probably essential for corneal homeostasis.

Ketamine/Xylazine-Induced Corneal Damage in Mice

“…[ 21 ] No lesions were observed in rats administered ketamine or xylazine alone, nor if rats were treated with yohimbine during recovery. Similar results in rats were subsequently reported by Tita et al[ 22 ] and Turner and Albassam who additionally showed that if rats were anesthetized with isoflurane instead of ketamine/xylazine, damage was avoided completely. [ 23 ] Similar to our observations, these studies using rats injected with ketamine/xylazine reported damage involving central corneal opacities and seem likely to indicate that the same deleterious side-effect we have observed occurs in multiple rodent species.…”

Visible light induces matrix metalloproteinase‐9 expression in rat eye

“…The successive elevation of MMP-9 mRNA in these eye structures could suggest an indirect mechanism of MMP-induction through diffusible factors originating in the photosensitive retina, similar to the paracrine induction of some MMPs described in tumor progression models (Tang et al 2004). In the case of cornea, the MMP-9 elevation was partly an effect of systemic xylazine administration as shown by control experiments, and could be the basis of corneal toxicity of xylazine seen in other studies (Tita et al 2001). There is a possibility of light absorbance by the transparent media of the eye to reach the level of cellular stress and initiate pro-MMP-9 induction by resident or inflammatory cells in each of these eye structures, but various optical radiation-bands are differentially absorbed by ocular media.…”

“…2004). In the case of cornea, the MMP‐9 elevation was partly an effect of systemic xylazine administration as shown by control experiments, and could be the basis of corneal toxicity of xylazine seen in other studies (Tita et al. 2001).…”

Xylazine-induced reduction of tissue sensitivity to insulin leads to acute hyperglycemia in diabetic and normoglycemic monkeys

“…Xylazine is an α 2 -adrenoceptor agonist and shares the similar pharmacological properties with clonidine [1-4]. It has been widely used as a drug for sedation and analgesia in veterinary clinic and non-human mammal research for several decades [5,6].…”