Effects of coadministration of cannabinoids and morphine on nociceptive behaviour, brain monoamines and HPA axis activity in a rat model of persistent pain D. P. Finn, S. R. G. Beckett, C. H. Roe, A. Madjd, K. C. F. Fone, D. A. Kendall, C. A. Marsden and V. Chapman Institute of Neuroscience, School of Biomedical Sciences, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK Keywords: cannabidiol, corticosterone, D 9 -tetrahydrocannabinol, formalin, morphine Abstract The antinociceptive effects of D 9 -tetrahydrocannabinol (D 9 -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 D 9 -THC (1 or 2.5 mg/kg), cannabidiol (5 mg/kg), morphine (2 mg/kg), D 9 -THC  morphine, D 9 -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. D 9 -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 D 9 -THC. Morphine reduced both phases of formalin-evoked nociceptive behaviour. Coadministration of D 9 -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 D 9 -THC and morphine alone occurred at doses devoid of effects on locomotor activity, coadministration of D 9 -THC and morphine inhibited locomotor activity. In conclusion, coadministration of a low dose of morphine, but not cannabidiol, with D 9 -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. Introduction Cannabinoid receptor agonists such as D 9 -tetrahydrocannabinol (D 9 - THC) produce a tetrad of behaviour consisting of antinociception, hypolocomotor activity, hypothermia and catalepsy (Martin et al., 1991). Antinociceptive effects of D 9 -THC in models of acute pain (for review see Pertwee, 2001) and tonic persistent pain (Moss & Johnson, 1980) have been described. Cannabis extracts rich in D 9 -THC and another natural cannabinoid, cannabidiol (CBD), are effective analge- sics in chronic pain patients (Wade et al., 2003). CBD also blocks anxiety, and other subjective alterations, induced by D 9 -THC in humans (Zuardi et al., 1982). Thus, CBD, or cannabis extracts rich in CBD, may have a reduced side-effect pro®le. The data from animal studies are, however, equivocal, with reports of CBD potentiating (Karniol & Carlini, 1973) or antagonizing (Welburn et al., 1976) the antinociceptive effects of D 9 -THC. In addition, systemic administra- tion of CBD is not antinociceptive in models of acute pain (Karniol & Carlini, 1973; So®a et al., 1975; Welburn et al., 1976; Sanders et al., 1979). To date, animal studies of CBD have used models of acute pain, which may explain discrepancies between clinical and animal-based research. Opioid receptor agonists are extremely effective analgesics, but are associated with undesirable side-effects (Nicholson, 2003). Coadmi- nistration of opioid and cannabinoid receptor agonists produces enhanced antinociceptive effects, compared with either drug alone, in models of acute pain (Welch & Eads, 1999; Cichewicz & McCarthy, 2003). Synergism occurs at subeffective or submaximal doses of cannabinoid or opioid agonists and these effects are blocked by cannabinoid receptor 1 (CB 1 ) and opioid receptor antagonists (Reche et al., 1996; Smith et al., 1998). However, it is unclear whether enhanced antinociceptive effects of opioids and cannabinoids occur in models of persistent pain, and whether secondary effects are also enhanced. The formalin model of tonic, persistent pain (Dubuisson & Dennis, 1977; Abbott et al., 1995) is characterized by biphasic paw-directed nociceptive behaviour, hypothalamo-pituitary-adrenal (HPA) axis acti- vation and alterations in brain monoamines (Pacak et al., 1995; Taylor et al., 1998; Palkovits et al., 1999). Intraplantar injection of formalin activates supra-spinal nociceptive pathways and increases immediate± early gene expression in the periaqueductal grey (PAG), thalamus and hypothalamus (Finn et al., 2003a; Pertovaara et al., 1993; Liu et al., 1998; Baulmann et al., 2000; Keay et al., 2002). Antinociceptive effects of systemically administered D 9 -THC and morphine are mediated by CB 1 receptors and m-opioid receptors located in these brain regions (Lichtman & Martin, 1997; Manning & Franklin, 1998). Furthermore, CB 1 receptors and m-opioid receptors modulate European Journal of Neuroscience, Vol. 19, pp. 678±686, 2004 ß Federation of European Neuroscience Societies doi:10.1111/j.1460-9568.2004.03177.x Correspondence: Dr David P. Finn, as above. E-mail: David.Finn@Nottingham.ac.uk Received 21 August 2003, revised 6 November 2003, accepted 4 December 2003