Effects of coadministration of cannabinoids and morphine on nociceptive behaviour, brain monoamines and HPA axis activity in a rat model of persistent pain

Abstract

The antinociceptive effects of Delta9-tetrahydrocannabinol (Delta9-THC) have been widely described; however, its therapeutic potential may be limited by secondary effects. We investigated whether coadministration of low doses of cannabinoids or cannabinoids and morphine produced antinociception in the absence of side-effects. Effects of preadministration (i.p.) of Delta9-THC (1 or 2.5 mg/kg), cannabidiol (5 mg/kg), morphine (2 mg/kg), Delta9-THC + morphine, Delta9-THC + cannabidiol or vehicle on formalin-evoked nociceptive behaviour were studied over 60 min. Trunk blood and brains were collected 60 min after formalin injection and assayed for corticosterone and tissue levels of monoamines and metabolites, respectively. Drug effects on locomotor activity, core body temperature and grooming were assessed. Delta9-THC reduced both phases of formalin-evoked nociceptive behaviour, enhanced the formalin-evoked corticosterone response and increased the 4-hydroxy-3-methoxyphenylglycol : noradrenaline ratio in the hypothalamus. Cannabidiol alone had no effect on these indices and did not modulate the effects of Delta9-THC. Morphine reduced both phases of formalin-evoked nociceptive behaviour. Coadministration of Delta9-THC and morphine reduced the second phase of formalin-evoked nociceptive behaviour to a greater extent than either drug alone, and increased levels of thalamic 5-hydroxytryptamine. While the antinociceptive effects of Delta9-THC and morphine alone occurred at doses devoid of effects on locomotor activity, coadministration of Delta9-THC and morphine inhibited locomotor activity. In conclusion, coadministration of a low dose of morphine, but not cannabidiol, with Delta9-THC, increased antinociception and 5-hydroxytryptamine levels in the thalamus in a model of persistent nociception. Nevertheless, these enhanced antinociceptive effects were associated with increased secondary effects on locomotor activity.

Dissociable Effects of the Cannabinoid Receptor Agonists Δ9-Tetrahydrocannabinol and CP55940 on Pain-Stimulated Versus Pain-Depressed Behavior in Rats

“…The antinociceptive effects of THC and CP55940 in the present study agree with a large literature showing that cannabinoid agonists produce antinociception in nearly all assays of pain-stimulated behavior (for recent reviews, see Rice, 2006;Karst et al, 2010). For example, previous studies in rodents have shown that cannabinoid agonists decreased stretching elicited by intraperitoneal acid administration (Sofia et al, 1975;Anikwue et al, 2002;Booker et al, 2009), first and second phases of nociceptive behavior elicited by intraplantar formalin injection (Finn et al, 2004;Khodayar et al, 2006), tail-flick/paw-withdrawal responses elicited by noxious heat (Lichtman and Martin, 1991;De Vry et al, 2004;Wiley et al, 2007), and hypersensitive withdrawal responses elicited by thermal/mechanical stimuli in inflammatory or neuropathic pain models (Cheng and Hitchcock, 2007;Elikkottil et al, 2009;Sain et al, 2009). As in the present study, cannabinoid antinociception is often shown to be dose-and/or time-dependent, and sensitivity to rimonabant antagonism or genetic knockout of cannabinoid 1 receptors has been interpreted as evidence of cannabinoid 1 receptor mediation (Monory et al, 2007;Booker et al, 2009).…”

“…As in the present study, cannabinoid antinociception is often shown to be dose-and/or time-dependent, and sensitivity to rimonabant antagonism or genetic knockout of cannabinoid 1 receptors has been interpreted as evidence of cannabinoid 1 receptor mediation (Monory et al, 2007;Booker et al, 2009). It is generally appreciated that nonselective behavioral depression may confound measures of cannabinoid antinociception in assays of pain-stimulated behavior (De Vry et al, 2004;Finn et al, 2004), and in the present study, THC and CP55940 produced evidence of nonselective behavioral depression insofar as they decreased ICSS in the absence of pain. However, THC-induced depression of acid-stimulated stretching was longer lasting than THC-induced depression of control ICSS.…”

“…However, decreases in painstimulated behavior can be produced either by a reduction in sensory sensitivity to the noxious stimulus (true analgesia) or nonselective behavioral depressant effects (sedation, motor impairment) that limit the subject's ability to respond. Sedative drugs such as cannabinoid agonists are especially prone to producing false-positive antinociception in assays of pain-stimulated behavior (De Vry et al, 2004;Finn et al, 2004). In contrast, pain-depressed behaviors are defined as behaviors such as feeding, locomotion, or operant behavior that decrease in rate or intensity after delivery of a noxious stimulus.…”

Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities

“…Thus, for example, additive or synergistic interactions resulting in antinociception have been reported to occur in the rat formalin paw model of inflammatory pain between -intraperitoneal D 9 -THC and morphine [72]; -intrathecal R-(þ)-WIN55212 and an intrathecally administered a 2 -adrenoceptor agonist (clonidine), cholinesterase inhibitor (neostigmine) or local anaesthetic (bupivicaine) [73,74]; -anandamide and the cyclooxygenase inhibitor, ibuprofen, administered by intraplantar injection [75]; and -HU-210 and the non-steroidal anti-inflammatory drug, acetylsalicylic acid, co-administered systemically [76].…”

Δ9-Tetrahydrocannbinol Accounts for the Antinociceptive, Hypothermic, and Cataleptic Effects of Marijuana in Mice

“…However, these interactions are usually only seen at doses of CBD that are as high or higher than the dose of ⌬ 9 -THC, a combination that is not often the case with recreationally available marijuana (e.g., ElSohly et al, 2000). Also, several studies have reported opposite or no such interactions between ⌬ 9 -THC and CBD (e.g., Welburn et al, 1976;Jarbe et al, 1977;Zuardi et al, 1984;Fadda et al, 2004;Finn et al, 2004). Other constituents of marijuana have also been evaluated for their own activity and their ability to modulate the effects of ⌬ 9 -THC.…”