The periaqueductal gray contributes to bidirectional enhancement of antinociception between morphine and cannabinoids

Abstract

Co-administration of opioids and cannabinoids can enhance pain relief even when administered on different days. Repeated systemic administration of morphine has been shown to enhance the antinociceptive effect of tetrahydrocannbinol (THC) administered 12 hours later, and repeated microinjection of the cannabinoid receptor agonist HU-210 into the ventrolateral periaqueductal gray (PAG) has been shown to enhance the antinociceptive effect of morphine administered one day later. The primary objective of the present study was to test the hypotheses that this cannabinoid/opioid interaction is bidirectional. Experiment 1 showed that microinjection of morphine into the ventrolateral PAG of male Sprague-Dawley rats twice daily for 2 days enhanced the antinociceptive effect of HU-210 measured one day later. In Experiment 2, twice daily systemic injections of THC enhanced the antinociceptive effect of morphine administered one day later. These results complement the previously mentioned studies by showing that morphine and cannabinoid interactions are bidirectional and that the ventrolateral PAG plays an important role in this effect. In contrast to the PAG, repeated administration of HU-210 or the cannabinoid receptor agonist, WIN 55,212-2, into the RVM had a neurotoxic effect. Rats became ill following repeated cannabinoid administration whether given alone or with morphine. Presumably, this neurotoxic effect was caused by the high cannabinoid concentration following RVM microinjection because rats did not become ill following repeated systemic THC administration. These findings indicate that alternating opioid and cannabinoid treatment could produce a longer lasting and more potent analgesia than either compound given alone.

Role of TRPV1 channels of the dorsal periaqueductal gray in the modulation of nociception and open elevated plus maze-induced antinociception in mice

“…It is noteworthy, however, that many other neurotransmitter systems (e.g., serotonin [52], opioids [53,54], cannabinoids [17,55], etc.) located within the PAG have also been implicated in the modulation of nociception and various forms of stress-induced antinociception.…”

Effects of centrally administered endocannabinoids and opioids on orofacial pain perception in rats

“…Allosteric modulators of CB 1 receptors may therefore be a useful strategy for amplifying effects of ECs only at sites where they are produced and released on demand (Laprairie et al, 2017). Nonetheless, multifunctional compounds targeting the ECS allied to inhibition of COX2 (Grim et al, 2014), antagonism of TRPV1 (Maione et al, 2006; or in combination with opioids (Wilson-Poe et al, 2013) or non-steroidal anti-inflammatory drugs (Guindon et al, 2006) have great potential to produce a superior therapeutic profile with minimized unwanted cannabimimetic side effects. A novel therapeutic approach in many pathological states can be the possible modulation of EC activity through the regulation of their synthesis or degradation.…”

“…Pharmacological treatment of orofacial pain is difficult and controversial (Tzabazis et al, 2014;Weiss et al, 2017). It has been demonstrated that the endogenous opioid system could be involved in cannabinoid antinociception, and recent data have also provided evidence for a role of the endogenous cannabinoid system in opioid antinociception (Cichewicz, 2004;Bushlin et al, 2010;Wilson-Poe et al, 2013).…”

“…Pharmacological treatment of orofacial pain is difficult and controversial (Tzabazis et al, 2014;Weiss et al, 2017). It has been demonstrated that the endogenous opioid system could be involved in cannabinoid antinociception, and recent data have also provided evidence for a role of the endogenous cannabinoid system in opioid antinociception (Cichewicz, 2004;Bushlin et al, 2010;Wilson-Poe et al, 2013).The opioid receptor system includes three subtypes of receptors, μ, δ and κ, and the endogenous opioid peptides, β-endorphin, enkephalins, dynorphins and endomorphins, that can activate these receptors (Kieffer, 1995). The cannabinoid system comprises the two major cannabinoid receptors, CB 1 and CB 2 receptors, their endogenous ligands, anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which regulate their biosynthesis and degradation (Di Marzo et al, 2004).…”

Effects of Cannabidiol and a Novel Cannabidiol Analog against Tactile Allodynia in a Murine Model of Cisplatin-Induced Neuropathy: Enhanced Effects of Sub-Analgesic Doses of Morphine

“…Evidence suggests that a dual pharmacotherapy at these targets may increase CB-mediated analgesic effects [13][14][15][16]. For example, the CB1 agonist THC shows synergistic effects with sub-analgesic doses of the μ-opioid agonist morphine in a rat arthritic pain model [17].…”