Antinociceptive action of cannabidiol on thermal sensitivity and post-operative pain in male and female rats.

This study investigated the antinociceptive potential of cannabidiol (CBD) in male and female Wistar rats. The assessment and analysis included tail withdrawal to thermal stimulation (tail flick test) and mechanical allodynia induced by plantar incision injury (von Frey test). CBD reduced acute thermal sensitivity in uninjured animals and post-operative mechanical allodynia in males and females. In the tail flick test, CBD 30 mg/kg i.p. was required to induce antinociception in males. During the proestrus phase, females did not show a statistically significant antinociceptive response to CBD treatment despite a noticeable trend. In contrast, in a separate group of rats tested during the late diestrus phase, antinociception varied with CBD dosage and time. In the post-operative pain model, CBD at 3 mg/kg decreased mechanical allodynia in males. Similarly, this dose reduced allodynia in females during proestrus. However, in females during late diestrus, the lower dose of CBD (0.3 mg/kg) reduced mechanical allodynia, although the latency to onset of the effect was slower (90 min). The effectiveness of a 10-fold lower dose of CBD during the late diestrus stage in females suggests that ovarian hormones can influence the action of CBD. While CBD has potential for alleviating pain in humans, personalized dosing regimens may need to be developed to treat pain in women.

100-Hz Electroacupuncture but not 2-Hz Electroacupuncture is Preemptive Against Postincision Pain in Rats.

Preemptive analgesia involves introducing an analgesic before noxious stimulation. Electroacupuncture (EA) activates descending mechanisms that modulate nociceptive inputs into the spinal dorsal horn. This study evaluated whether preoperative EA is more effective than postoperative EA in reducing incision pain in rats. The nociceptive threshold to mechanical stimulation was utilized to examine the effects of an intraperitoneal injection of saline (0.1 mL/kg) or naloxone (1 mg/kg) on antinociception induced by a 20-minute period of 2-Hz or 100-Hz EA applied to the Zusanli (ST36) and Sanyinjiao (SP6) acupoints before surgical incision, or 10 minutes after or 100 minutes after surgical incision of the hind paw. The extent of mechanical hyperalgesia after the incision was significantly attenuated by the application of 100-Hz EA preoperatively, but not by its application at 10 minutes or 100 minutes postoperatively. By contrast, 2-Hz EA was effective against postoperative hyperalgesia when applied 10 minutes or 100 minutes after surgery but not when it was applied preoperatively. Only the effect of 2-Hz EA applied 10 minutes after surgery was sensitive to naloxone. The present study showed for the first time that 100-Hz EA, but not 2-Hz EA, exerts a nonopioidergic preemptive effect against postincision pain in rats.

Electroacupuncture at 2/100 hz activates antinociceptive spinal mechanisms different from those activated by electroacupuncture at 2 and 100 hz in responder rats.

We examined the effects of intrathecal injection of desipramine and fluoxetine (selective inhibitors of norepinephrine and 5-HT uptake, resp.), thiorphan and neostigmine (inhibitors of enkephalinase and acetylcholinesterase, resp.), gabapentin (a GABA releaser), and vigabatrin (an inhibitor of GABA-transaminase) on the antinociception induced by 2 Hz, 100 Hz, or 2/100 Hz electroacupuncture (EA) applied bilaterally to the Zusanli (ST36) and Sanyinjiao (SP6) acupoints using the rat tail-flick test. We show that 2 Hz EA antinociception lasts longer after the administration of drugs that increase the spinal availability of norepinephrine, acetylcholine, or GABA; 100 Hz EA antinociception lasts longer after drug that increases the spinal availability of norepinephrine; 2/100 Hz EA antinociception lasts longer after drugs that increase the spinal availability of endogenous opioids or GABA. We conclude that the antinociceptive effect of 2/100 Hz EA is different from the synergistic effect of alternate stimulation at 2 and 100 Hz because the effect of the former is not changed by increasing the spinal availability of serotonin and lasts longer after the administration of vigabatrin. The combination of EA with drugs that increase the availability of spinal neurotransmitters involved in the modulation of nociceptive inputs may result in a synergistic antinociceptive effect in the rat tail-flick test.

The effect of intrathecal gabapentin on neuropathic pain is independent of the integrity of the dorsolateral funiculus in rats.

AIM: This study evaluates the contribution of inhibitory pain pathways that descend to the spinal cord through the dorsolateral funiculus (DLF) on the effect of intrathecal gabapentin against spinal nerve ligation (SNL)-induced behavioral hypersensitivity to mechanical stimulation in rats. MAIN METHOD: Rats were submitted to a sham or complete ligation of the right L5 and L6 spinal nerves and a sham or complete DLF lesion. Next, the changes induced by intrathecal administration of gabapentin on the paw withdrawal threshold of rats to mechanical stimulation were evaluated electronically. KEY FINDINGS: Intrathecal gabapentin (200µg/5µl) that was injected 2 or 7days after surgery fully inhibited the SNL-induced behavioral hypersensitivity to mechanical stimulation in sham DLF-lesioned rats; gabapentin was effective against the SNL-induced behavioral hypersensitivity to mechanical stimulation also in DLF-lesioned rats. SIGNIFICANCE: The effect of intrathecally administered gabapentin against SNL-induced behavioral hypersensitivity to mechanical stimulation in rats does not depend on the activation of nerve fibers that descend to the spinal cord via the DLF.

Modulation of persistent nociceptive inputs in the anterior pretectal nucleus of the rat.

The anterior pretectal nucleus (APtN) participates in nociceptive and antinociceptive mechanisms. Drugs were injected into the ventral APtN to evaluate how intrinsic mechanisms interact in the nucleus during persistent allodynia produced by a surgical incision in a rat hind paw. Naloxone (1 and 10 ng/0.08 microl), methysergide (0.037 and 3.7 ng/0.08 microl) or atropine (0.1 and 10 ng/0.08 microl) increased the allodynia. The effect of methysergide was intensified by naloxone or atropine, the effect of atropine was intensified by naloxone or methysergide, but the effect of naloxone was not changed by methysergide or atropine. DAMGO (1.5 microg/0.08 microl), oxotremorine (5 microg/0.08 microl) or serotonin (5 microg/0.08 microl) reduced the allodynia. The effect of DAMGO was less intense in methysergide-treated rats but was not changed in atropine-treated rats, the effect of serotonin was not changed by naloxone or atropine, and the effect of oxotremorine was not changed by naloxone or methysergide. Baclofen (150 ng/0.08 microl) increased, whereas phaclofen (300 ng/0.1 microl) reduced the allodynia. Bicuculline (50 ng/0.08 microl) increased the incision pain, while muscimol (50 ng/0.08 microl) did not change it. Phaclofen was inhibited by methysergide but was unchanged by atropine. The effect of DAMGO was reduced by phaclofen (100 ng/0.1 microl). We interpret these results as indicative that noxious inputs utilize cholinergic and serotonergic pathways in the vAPtN for the activation of descending pain control mechanisms, the serotonergic pathway being under the control of GABAergic neurons which, in turn, are modulated negatively by opioid nerve terminals.

Effects of intrathecal L-and N-type calcium channel blockers on the antinociception evoked by opioid agonists in the rat tail flick test

The effects of intrathecal administration of nimodipine or omega-conotoxin GVIA(L- and N-type calcium channel blockers, respectively) alone or followed by DAMGO, DADLE or bremazocine (mu-, delta- and kappa- opioid agonists, respectively) were studied on the rat tail flick test. The N- (16 to 64 pmoles), but not the L-type blocker (60 to 240 pmoles) produced a dose and time-dependent increase in the latency for the tail-flick reflex. DAMGO (30 to 120 pmoles) or bremazocine (190 to 560 pmoles), but not DADLE (50 to 200 pmoles), produced a dose-dependent increase in the latency for the tail-flick reflex. The effect of the highest dose of DAMGO was smaller, while the effects of DADLE and bremazocine were not changed after nimodipine (60 pmoles). The effects of DADLE were significantly potentiated, while the effects of DAMGO and bremazocine were not changed after omega-conotoxin GVIA (16 pmoles). The intrathecal administration of an N-type calcium channel blocker with a delta-opioid agonist seems to be the most effective combination to produce antinociception in the rat tail flick test.

Effects of intrathecal L-and N-type calcium channel blockers on the antinociception evoked by opioid agonists in the rat tail flick test

The effects of intrathecal administration of nimodipine or omega-conotoxin GVIA(L- and N-type calcium channel blockers, respectively) alone or followed by DAMGO, DADLE or bremazocine (mu-, delta- and kappa- opioid agonists, respectively) were studied on the rat tail flick test. The N- (16 to 64 pmoles), but not the L-type blocker (60 to 240 pmoles) produced a dose and time-dependent increase in the latency for the tail-flick reflex. DAMGO (30 to 120 pmoles) or bremazocine (190 to 560 pmoles), but not DADLE (50 to 200 pmoles), produced a dose-dependent increase in the latency for the tail-flick reflex. The effect of the highest dose of DAMGO was smaller, while the effects of DADLE and bremazocine were not changed after nimodipine (60 pmoles). The effects of DADLE were significantly potentiated, while the effects of DAMGO and bremazocine were not changed after omega-conotoxin GVIA (16 pmoles). The intrathecal administration of an N-type calcium channel blocker with a delta-opioid agonist seems to be the most effective combination to produce antinociception in the rat tail flick test. (AU)

Controle da dor pós-operatória / Control of postoperative pain

No presente artigo, säo apresentadas a fisiopatologia da dor aguda pós-operatória e a importância clínica de seu controle sobre a morbidade e resultado cirúrgico. Também, säo apresentados os métodos de analgesia pós-operatória, atualmente empregados pelos membros do "Serviço de Anestesiologia do Hospital das Clínicas de Ribeiräo Preto-USP", as melhores estratégias e as bases racionais para seu uso efetivo.