Cannabinoid CB₁ receptors mediate the effects of dipyrone

Abstract

Dipyrone is a non-steroidal anti-inflammatory drug used primarily as an analgesic and antipyretic. Some hypothesize that dipyrone activity can modulate other pathways, including endocannabinoid signalling. Thus, the aim of the present study was to evaluate the possible role of endocannabinoids in mediating dipyrone activity. This study is based on the tetrad effects of cannabinoids, namely an antinociceptive and cataleptic state, hypolocomotion and hypothermia. Dipyrone (500 mg/kg, i.p.) treatment decreased locomotor activity, increased the latency to a thermal analgesic response and induced a cataleptic and hypothermic state. These reactions are similar to the tetrad effects caused by the cannabinoid agonist WIN 55,212-2 (3 mg/kg, i.p.). The cannabinoid CB1 receptor antagonist AM251 (10 mg/kg, i.p.) reversed the effects of dipyrone on locomotor activity, the cataleptic response and thermal analgesia. Both AM251 (10 mg/kg, i.p.) and the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine (10 mg/kg, i.p.) accentuated the reduction in body temperature caused by dipyrone. However, the CB2 receptor antagonist AM630 did not alter the hypothermic response to dipyrone. These results indicate involvement of the endocannabinoid system, especially CB1 receptors, in the analgesic and cataleptic effects of dipyrone, as well as hypolocomotion. However, cannabinoid receptors and TRPV1 were not involved in the hypothermic effects of dipyrone. We hypothesize that the mechanism of action of dipyrone may involve inhibition of cyclo-oxygenase and fatty acid amide hydrolase, which together provide additional arachidonic acid as substrate for endocannabinoid synthesis or other related molecules. This increase in endocannabinoid availability enhances CB1 receptor stimulation, contributing to the observed effects.

Pharmacokinetic profiles of the active metamizole metabolites after four different routes of administration in healthy dogs

“…In partial explanation for this action, MT has been shown to interact with both the N-methyl-D-aspartate receptor and the opioid system; however, the exact mechanism by which MT produces its analgesic action remains unclear (Khodai, 2008;Tortorici, Vasquez, & Vanegas, 1996). Recent studies have demonstrated that its analgesic action could partially be due to the interaction with the cannabinoid receptors (Crunfli, Vilela, & Giusti-Paiva, 2015;dos Santos et al, 2014). MT is available in human and veterinary markets in several countries (South America, Asia, and European countries) but has been withdrawn in other countries (Australia, USA, Sweden, Japan, Iran, and UK) because of safety concerns in humans.…”

Maternal dipyrone treatment during lactation in mice reduces maternal behavior and increases anxiety‐like behavior in offspring

“…The treatment with dipyrone during the first week of lactation had consequences on dams: disturbed maternal behavior was observed at all 3 doses used, and a reduction in locomotor activity was observed only at the doses of 300 and 500 mg/kg. In fact, a single intraperitoneal administration of dipyrone at 500 mg/kg reduced locomotor activity in male mice (Crunfli et al, 2015). In our study, the reduction in mobility does not seem to have influenced the reduction of maternal parameters evaluated (arched nursing and licking pups) since these parameters are not directly dependent on animal locomotion.…”

Cannabinoid Receptors Are Not Involved in Antinociception Induced by Systemic Diclofenac in Mice

“…As we have stated in the introduction, all NSAIDs have the potential of augmenting endocannabinoid levels by inhibiting COX-2 (although with a weak potential) and thereby preventing degradation of endocannabinoids (6,7,22). Inhibition of COX enzymes by NSAIDs may also elevate endocannabinoid synthesis due to the availability of arachidonic acid for endocannabinoid synthesis rather than prostaglandin synthesis (6,7,22). Moreover, some of the classical NSAIDs have been shown to inhibit FAAH directly and reduce the breakdown of endocannabinoids (9).…”

“…Moreover, some of the classical NSAIDs have been shown to inhibit FAAH directly and reduce the breakdown of endocannabinoids (9). Finally, inhibition of nitric oxide (NO) by NSAIDs may also attenuate the activation of endocannabinoid transporters and thus augment endocannabinoid levels (6,22). In addition to its well-known COX inhibitory activity, this final mechanism can be attributed to the antinociceptive effect of diclofenac, since NO-cGMP-K+ channel pathway has been suggested to be involved in the peripheral antinociceptive effect of diclofenac (23).…”

“…Recent investigations suggest that cannabinoid receptors and augmentation of endocannabinoid activity play important roles in the antinociceptive effects of both paracetamol and dipyrone (4,5). Besides paracetamol and dipyrone, all NSAIDs are expected to increase endocannabinoid tonus both by inhibiting endocannabinoid degradation and by increasing their synthesis via COX inhibition (6,7). Accordingly, it has been proposed that the endocannabinoid system appears to be involved in the antinociceptive effect of some NSAIDs, although there are contradictory findings (6)(7)(8)(9)(10)13).…”