Involvement of ATP-Sensitive K+ Channels in the Peripheral Antinociceptive Effect Induced by the α2-Adrenoceptor Agonist Xylazine

Abstract

Abstract. Xylazine is an α 2 -adrenergic agonist extensively used in veterinary medicine and animal experimentation for producing antinociception, sedation, and muscle relaxation. The nitric oxide (NO) / cGMP / ATP-sensitive K + (K ATP ) channel pathway has been proposed as the action mechanism of peripheral antinociception of several groups of drugs, including opioids and nonsteroidal analgesics. Considering the lack of knowledge regarding the mechanisms involved in xylazine effects, the present study investigated the contribution of K + channels on peripheral antinociception induced by xylazine using the rat paw pressure test, in which hyperalgesia was induced by intraplantar injection of prostaglandin E 2 . Xylazine administered into the right hind paw elicited a local antinociceptive effect, since only much higher doses produced a systemic effect in the contralateral paw. The peripheral antinociceptive effect induced by xylazine was antagonized by glibenclamide, a specific blocker of K ATP channels. In another experiment, tetraethylammonium, a voltage-dependent K + -channel blocker, and paxilline and dequalinium, which are selective blockers for the large-and small-conductance Ca 2+ -activated K + channels, respectively, were ineffective at blocking xylazine antinociception. These results provide evidence that the peripheral antinociceptive effect of xylazine probably results from K ATP -channel activation, while the voltage-dependent K + channels, small-and large-conductance Ca 2+-activated K + channels, appear not to be involved in this mechanism.

TRPV1 channel inhibition contributes to the antinociceptive effects of Croton macrostachyus extract in mice

“…Opening of the ATP-sensitive potassium channels (K- ATP ) have been shown as the end mechanism of the peripheral effect of many analgesics such as morphine [ 28 ], dypirone [ 29 ], diclofenac [ 30 ], xylazine [ 31 ], sildenafil [ 32 ] and even plant derivatives [ 11 ]. In order to determine whether or not this pathway is involved in the activity of MECM, its antinociceptive effect was evaluated in animals previously treated with glibenclamide, an inhibitor of K- ATP channels.…”

Mu, Delta, and Kappa opioid receptor agonists induce peripheral antinociception by activation of endogenous noradrenergic system

“…The opioid receptor and α 2 adrenoceptor agonists were involved in presynaptic modulation in the primary afferent neuron, inducing peripheral antinociception via similar mechanisms, inhibiting postsynaptic membrane excitation, releasing Ca 2+ ‐inducing neurotransmitters (see Yaksh,1985; Fürst,1999), and opening the ATP‐sensitive K + channels (Rodrigues and Duarte,2000; Amarante et al,2004; Pacheco and Duarte,2005; Romero and Duarte,2009).…”

CB1 and CB2 Cannabinoid Receptor Agonists Induce Peripheral Antinociception by Activation of the Endogenous Noradrenergic System

“…4 Data obtained by our group demonstrated that the peripheral antinociceptive effect of the adrenoceptor agonist xylazine involves the activation of α 2C adrenoreceptor 5 thus inducing nitric oxide synthase to produce nitric oxide with a subsequent increase of cyclic guanosine monophosphate in peripheral nociceptors 6 and opening of adenosine triphosphate-sensitive K + channels. 7 Activation of the β adrenoceptor is responsible for analgesia in patients with rheumatoid arthritis 8 and in rats with adjuvant-induced arthritis. 9,10 In addition, norepinephrine injected directly into inflamed rat hindpaw, via immune cells participation, produced dose-dependent antinociception, blocked by α 1 , α 2 , and β 2 adrenoceptor antagonists.…”

“…[19][20][21] First, both α 2 adrenoceptor and cannabinoid receptors induce antinociception through inhibition of postsynaptic membrane excitation, Ca 2+ -inducing neurotransmitter release, [22][23][24] and the opening of adenosine triphosphate-sensitive K + channels. 7,25 Second, some cannabinoid receptor agonists, such as N-palmitoylethanolamine (PEA), release norepinephrine in the central nervous system, inducing antinociception. 19 Third, there is synergy in the antinociceptive effect between the cannabinoid agonist WIN 55,212-2 and the α 2 adrenoceptor agonist clonidine at the spinal level.…”