Abstract
The endocannabinoid system is thought to modulate nociceptive signaling making it a potential therapeutic target for treating pain. However, there is evidence that endocannabinoids have both pro- and anti-nociceptive effects. In previous studies using Hirudo verbana (the medicinal leech), endocannabinoids were found to depress nociceptive synapses, but enhance non-nociceptive synapses. Here we examined whether endocannabinoids have similar bidirectional effects on behavioral responses to nociceptive vs. non-nociceptive stimuli in vivo. Hirudo were injected with either the 2-arachidonoylglycerol (2-AG) or anandamide and tested for changes in response to nociceptive and non-nociceptive stimuli. Both endocannabinoids enhanced responses to non-nociceptive stimuli and reduced responses to nociceptive stimuli. These pro- and anti-nociceptive effects were blocked by co-injection of a TRPV channel inhibitor, which are thought to function as an endocannabinoid receptor. In experiments to determine the effects of endocannabinoids on animals that had undergone injury-induced sensitization, 2-AG and anandamide diminished sensitization to nociceptive stimuli although the effects of 2-AG were longer lasting. Sensitized responses to non-nociceptive stimuli were unaffected 2-AG or anandamide. These results provide evidence that endocannabinoids can have opposing effects on nociceptive vs. non-nociceptive pathways and suggest that cannabinoid-based therapies may be more appropriate for treating pain disorders in which hyperalgesia and not allodynia is the primary symptom.
Highlights
The major barrier in understanding the pro- and anti-nociceptive effects of endocannabinoids is linking the behavioral effects to specific elements of the nociceptive circuitry
A post-hoc comparison confirmed that the normalize response threshold of 75 μM 2-AG group (N = 5) was significantly lower when compared to the dimethyl sulfoxide (DMSO) control group (N = 12)
A post-hoc comparison confirmed that the normalize response threshold of 100 μM anandamide group (N = 6) was significantly lower when compared to the DMSO control group (N = 11; P < 0.001)
Summary
The major barrier in understanding the pro- and anti-nociceptive effects of endocannabinoids is linking the behavioral effects to specific elements of the nociceptive circuitry. Previous studies in Hirudo have shown that 2-AG and anandamide elicit long-lasting (≥1 hr) depression in nociceptive N cell synapses and potentiation in non-nociceptive P cell synapses (summarized in Fig. 1A)[30,31,32,33,34,35]. These studies suggest that endocannabinoid effects on both synapses are mediated by a TRPV-like channel. The current study examined the effects of 2-AG and anandamide on behaviors elicited by non-nociceptive vs nociceptive stimuli in vivo. In animals that had undergone injury-induced sensitization, 2-AG and anandamide reversed the sensitized responses to nociceptive stimuli, but had no effect on sensitized responses to non-nociceptive stimuli
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