As adrenaline, serotonin and norepinephrine are two other vasoconstrictors and both of which have been proved to increase the quality and duration of local anesthetics when added as adjuvants. However, the difference in the improvement of the nociception of local anesthetics between the two adjuvants remains unclear. The purpose of this study was to assess the cutaneous nociception of mexiletine by coadministration with serotonin and norepinephrine. Subcutaneous injection of drugs or combinations includes mexiletine 0.6, 1.8, 6.0 μmol, serotonin 1.6500 μmol, noradrenaline 0.8895 nmol, saline, mexiletine 1.8 and 6.0 μmol, respectively combined with serotonin 0.4125, 0.8250, 1.6500 μmol and noradrenaline 0.0356, 0.1779, 0.8895 nmol, with each injection dose of 0.6 ml. The nociception of mexiletine alone and mexiletine coadministered with serotonin and norepinephrine was assessed after subcutaneous injection. Subcutaneous injections of mexiletine elicited dose-related cutaneous antinociception (P < 0.05, 0.01, or 0.001). Compared with mexiletine (1.8 μmol), adding norepinephrine (except for lowest dose) and serotonin to mexiletine (1.8 μmol) solutions for skin nociceptive block potentiated and prolonged the action (P < 0.01 or 0.001). Mexiletine (6.0 μmol) combined with norepinephrine and serotonin extended the duration of cutaneous antinociception when compared with mexiletine (6.0 μmol) alone (P < 0.05, 0.01, or 0.001). Both serotonin and norepinephrine improve the sensory block and enhances the nociceptive block duration of mexiletine, and serotonin is superior to that of norepinephrine.

BACKGROUND: Adrenaline (Adr) and dexmedetomidine (Dex) are commonly used adjuvants of local anesthetics; however, the difference in the improvement of analgesia of local anesthetics between the 2 adjuvants remains unclear.
OBJECTIVE: The objective of this experimental research was to evaluate the cutaneous analgesic effect of mexiletine (Mex) by coadministration with Dex or Adr.
METHODS: The effect of a nociceptive block was assessed based on the inhibition of the cutaneous trunci muscle reflex in response to skin pinpricks in rats. The analgesic activity of Mex alone and Mex coadministered with Dex or Adr was evaluated after subcutaneous injections. Subcutaneous injections of drugs or combinations include Mex 0.6, 1.8, and 6.0 μmol; Adr 13.66 nmol; Dex 1.05600 nmol; saline; and Mex 1.8 and 6.0 μmol, respectively, combined with Dex 0.01056, 0.10560, and 1.05600 nmol or Adr 0.55, 2.73, and 13.66 nmol, with each injection dose of 0.6 mL.
RESULTS: Subcutaneous injections of Mex elicited dose-related cutaneous analgesia. Compared with Mex (1.8 μmol), adding Dex or Adr to Mex (1.8 μmol) solutions for skin nociceptive block potentiated and prolonged the action. Mex (6.0 μmol) combined with Dex or Adr extended the duration of cutaneous analgesia when compared with Mex (6.0 μmol) alone. A high dose of Adr is more effective with Mex 1.8 μmol than that of Dex, whereas medium and low doses were less effective. Mex 6.0 μmol combined with any dose of Adr is superior to that of Dex.
CONCLUSIONS: Both Dex and Adr improve the sensory block and enhance the nociceptive block duration of Mex. But in most cases, Adr is superior to Dex. It may be that different mechanisms of action of the 2 adjuvants lead to the differences.

Brompheniramine as an antihistamine blocked sodium channels, and local anesthetics by blocking sodium channels produced the local anesthetic effects. The authors aimed to assess local anesthetic quality and duration of brompheniramine when compared to the local anesthetic mepivacaine. After rats were shaved and injected subcutaneously on the dorsal skin, the panniculus reflex, induced via applying a noxious pinprick to the skin (injected area), was scored. The dose-response curve and nociceptive block duration of brompheniramine were constructed and compared with mepivacaine. The cutaneous analgesic effects in both brompheniramine and mepivacaine groups were concentration-dependent. On the basis of the amount required to produce a 50% block effect (ED50, 50% effective dose), the drug\'s potency was brompheniramine (0.89 [0.82-0.96] μmol) better than mepivacaine (2.45 [2.17-2.76] μmol) (P < 0.01). Full recovery time of brompheniramine was more prolonged than mepivacaine\'s (P < 0.01) on infiltrative cutaneous analgesia when comparing ED25s, ED50s and ED75s. Our preclinical data demonstrated that subcutaneous brompheniramine induces dose-relatedly analgesic effects, and brompheniramine induces prolonged analgesic duration when compared with mepivacaine. Brompheniramine also provokes better cutaneous analgesia than mepivacaine.

BACKGROUND: Dextrorphan with long-acting local anesthetic effects did not cause system toxicity as fast as bupivacaine, while catecholamines (i.e., epinephrine) with the vasoconstrictive characteristics enhanced the effects of local anesthetic drugs. The objective of the experiment was to examine the synergistic effect of local dopamine (a catecholamine) injection on cutaneous antinociception of dextrorphan.
METHODS: The panniculus reflex in response to skin stimulation with a needle was used as the primary endpoint when dextrorphan (1.50, 2.61, 5.46, 10.20 and 20.40 μmol) alone, dopamine (16.20, 32.40, 51.60, 60.00 and 81.60 μmol) alone, or dopamine + dextrorphan (a ratio of ED50vs. ED50) was injected subcutaneously on the rat\'s back. We used an isobolographic modelling approach to determine whether a synergistic effect would be observed.
RESULTS: We showed that dextrorphan, dopamine, or the mixture of dopamine and dextrorphan produced dose-related skin antinociception. The potency (ED50, 50% effective dose) for cutaneous antinociception was dextrorphan [6.02 (5.93-6.14) μmol] greater than dopamine [48.91 (48.80-49.06) μmol] (p < 0.01). The duration of nociceptive inhibition induced by dopamine was longer than that induced by dextrorphan (p <  0.01) based on their equipotent doses (ED25, ED50, and ED75). Enhancement and prolongation of skin antinociception occurred after co-administration of dopamine with dextrorphan.
CONCLUSIONS: When compared to dopamine, dextrorphan was more potent and had a shorter duration of skin nociceptive block. Dopamine produced a synergistic effect on dextrorphan-mediated antinociception, and prolonged dextrorphan\'s antinociceptive duration.

BACKGROUND: Pramoxine has been shown to produce spinal anesthesia, while cutaneous analgesia (peripheral) of pramoxine is not established. The experimental goal was to examine cutaneous antinociception produced by a local anesthetic (LA) pramoxine and compare this result with that of another well-known LA lidocaine.
METHODS: Cutaneous antinociception was evaluated by blockade of pinprick- induced cutaneous trunci muscle reflex (CTMR) on the skin of rat\'s back. After the dose-related curves were constructed, the quality and duration of drug\'s (lidocaine and pramoxine) cutaneous antinociception were compared.
RESULTS: We showed that pramoxine, as well as lidocaine produced skin antinociception in a dose-related fashion. The relative potency (ED50 [50% effective dose] basis) was lidocaine (5.44 [4.67-6.35] μmol) greater than pramoxine (42.1 [38.8-45.7] μmol) (p < 0.01). On the basis of equianalgesic doses (ED75, ED50, and ED25), pramoxine caused equivalent duration of cutaneous antinociception to lidocaine.
CONCLUSIONS: These preclinical data indicated that pramoxine elicits skin antinociception dose-relatedly. Pramoxine exhibits a potency less than that of lidocaine while they have a comparable duration of skin antinociceptive action.

The goal of the experimental design was to assess the cutaneous analgesic effect of mexiletine by co-injection with clonidine. The effect of nociceptive block was evaluated according to the inhibition of the cutaneous trunci muscle reflex (CTMR) in response to skin pinpricks in rats. The dose-related analgesic effect of mexiletine alone or mexiletine co-administrated with clonidine was constructed after subcutaneous injection. Subcutaneous injections of mexiletine elicited dose-related cutaneous analgesia. Compared with mexiletine (1.8μmol), adding clonidine to mexiletine (1.8μmol) solutions for skin nociceptive block potentiated and prolonged the action (p<0.01). Mexiletine (6μmol) combined with clonidine extended the duration of cutaneous analgesia when compared with mexiletine (6μmol) alone (p<0.01). Co-administration of clonidine increases the potency and extends the duration of cutaneous analgesia by mexiletine, and the minimal dose of clonidine to intensify the analgesic effect is 0.06μmol.