Epinephrine, phenylephrine, and methoxamine induce infiltrative anesthesia via alpha1-adrenoceptors in rats

Abstract

Aim: To assess whether epinephrine, phenylephrine, and methoxamine act via certain subtypes of adrenoceptors to exert their local anesthetic activity.

Methods: We investigated cutaneous anesthesia from adrenoceptor agonists and/or antagonists in conscious, unanesthetized Sprague-Dawley male rats (weight 200-250 g). Cutaneous anesthesia was evidenced by a block of the cutaneous trunci muscle reflex, which is characterized by reflex movement of the skin over the back produced by twitches of lateral thoracispinal muscles in response to local dorsal cutaneous noxious pinprick.

Results: Local infiltration of epinephrine, L-phenylephrine, or methoxamine alone induces cutaneous anesthesia in rats in a dose-dependent way. Epinephrine is found to be 19 and 29 times more potent than those of methoxamine and L-phenylephrine, respectively. The cutaneous anesthesia induced by epinephrine, phenylephrine, or methoxamine can be significantly reduced by alpha(1)-adrenoceptor antagonists (eg, prazosin), alpha1, alpha2-adrenoceptor antagonist, alpha(1A)-adrenoceptor antagonist (eg, 5-methylurapdil), alpha(1B)-adrenoceptor antagonist (eg, chloroethylclonidine), or alpha(1D)-adrenoceptor antagonist (eg, BMY7873).

Conclusion: Our results indicate that epinephrine, phenylephrine and methoxamine all act mainly via mixed subtypes of alpha(1)-adrenoceptors to induce cutaneous anesthesia in the rat.

Figure 1

(A) Time courses of inhibition of cutaneous trunci muscle reflex by epinephrine, phenylephrine, and methoxamine after subcutaneous injections of drugs in rats (n=6 rats for each drug). Values are mean±SEM. The injected volume was 0.6 mL. Neurological evaluations were done before, and 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, 90, 105, and 120 min after drug injection. (B) The dose-response curves of epinephrine, phenylephrine, and methoxamine on cutaneous analgesia in rats (n=6 rats at each testing point). Values are mean±SEM and were fitted with the SASNLIN analysis.

Figure 2

(A) Time courses of inhibition of cutaneous trunci muscle reflex by epinephrine (ED₈₀), phenylephrine (ED₈₀), and methoxamine (ED₈₀) in the presence of prazosine after subcutaneous injections of drugs in rats (n=6 rats for each drug). Values are mean±SEM. Prazosine (0.3 mL) was injected 5 min before the injection of epinephrine (0.3 mL), phenylephrine (0.3 mL), and methoxamine (0.3 mL). Neurological evaluations were done before, and 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, 90, 105, and 120 min after drug injection. (B) The dose-response curves of epinephrine, phenylephrine, and methoxamine in the presence of prazosine on cutaneous analgesia in rats (n=6 rats at each testing point). Values are mean±SEM and were fitted with the SASNLIN.

Figure 3

(A) Time courses of inhibition of cutaneous trunci muscle reflex by epinephrine, phenylephrine, and methoxamine in the presence of phentolamine after subcutaneous injections of drugs in rats (n=6 rats for each drug). Values are mean±SEM. Phentolamine (0.3 mL) was injected 5 min before the injection of epinephrine (0.3 mL), phenylephrine (0.3 mL), and methoxamine (0.3 mL). Neurological evaluations were done before, and 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, 90, 105, and 120 min after drug injection. (B) The dose-response curves of epinephrine, phenylephrine, and methoxamine in the presence of phentolamine on cutaneous analgesia in rats (n=6 rats at each testing point). Values are mean±SEM and were fitted with the SASNLIN.

Figure 4

(A) Time courses of inhibition of cutaneous trunci muscle reflex by epinephrine, phenylephrine, and methoxamine in the presence of 5-methylurapidil after subcutaneous injections of drugs in rats (n=6 rats for each drug). Values are mean±SEM. 5-Methylurapidil (0.3 mL) was injected 5 min before the injection of epinephrine (0.3 mL), phenylephrine (0.3 mL), and methoxamine (0.3 mL). Neurological evaluations were done before, and 5, 10, 15, 20, 25, 30, 40 , 50, 60, 75, 90, 105, and 120 min after drug injection. (B) The dose-response curves of epinephrine, phenylephrine, and methoxamine in the presence of 5-methylurapidil on cutaneous analgesia in rats (n=6 rats at each testing point). Values are mean±SEM and were fitted with the SASNLIN.

Figure 5

(A) Time courses of inhibition of cutaneous trunci muscle reflex by epinephrine, phenylephrine, and methoxamine in the presence of chloroethylclonidine (CEC) after subcutaneous injections of drugs in rats (n=6 rats for each drug). Values are mean±SEM. CEC (0.3 mL) was injected 5 min before the injection of epinephrine (0.3 mL), phenylephrine (0.3 mL), and methoxamine (0.3 mL). Neurological evaluations were done before, and 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, 90, 105, and 120 min after drug injection (B). The dose-response curves of epinephrine, phenylephrine, and methoxamine in the presence of CEC on cutaneous analgesia in rats (n=6 rats at each testing point). Values are mean±SEM and were fitted with the SASNLIN.

Figure 6

(A) Time courses of inhibition of cutaneous trunci muscle reflex by epinephrine, phenylephrine, and methoxamine in the presence of BMY7378 after subcutaneous injections of drugs in rats (n=6 rats for each drug). Values are mean±SEM. BMY7378 (0.3 mL) was injected 5 min before the injection of epinephrine (0.3 mL), phenylephrine (0.3 mL), and methoxamine (0.3 mL). Neurological evaluations were done before, and 5, 10, 15, 20, 25, 30, 40, 50, 60, 75, 90, 105, and 120 min after drug injection. (B) The dose-response curves of epinephrine, phenylephrine, and methoxamine in the presence of BMY7378 on cutaneous analgesia in rats (n=6 rats at each testing point). Values are mean±SEM and were fitted with the SASNLIN.