Decreased motivational properties of morphine in mouse models of cancerous- or inflammatory-chronic pain: Implication of supraspinal neuropeptide FF2 receptors

Abstract

Our main purpose was to evaluate the influence of cancer pain on the rewarding properties of morphine. Opioids are very addictive when used by healthy persons, conversely the occurrence of an opioid addiction seems very low when patients suffering from cancer are treated with morphine. We investigated the reinforcing properties of morphine in the place preference paradigm on a new model of mice suffering from a cancer pain induced by syngenic melanoma cells injected in the hind paw. These data were compared with mice suffering either from a short-term- or a chronic-inflammatory pain induced respectively by injection of carrageenan or complete Freund's adjuvant. Remarkably, mice suffering from cancer pain or chronic inflammatory pain did not develop any preference for the environment associated with the injection of morphine. In mice injected with melanoma cells, the specific binding of [(125)I]EYWSLAAPQRF-NH(2), an agonist of neuropeptide FF(2) receptors, was increased in several brain areas involved in the rewarding properties of opiates, including the shell of the nucleus accumbens, the major islands of Calleja, the ventral endopiriform nucleus and the amygdaloid area. Our study is the first to reveal a modification of morphine rewarding properties under cancer pain in rodents. We postulate that anti-opioid neuropeptides might contribute to the suppression of morphine rewarding effects in this murine model of cancer pain.

The Conditioned Place Preference Test for Assessing Welfare Consequences and Potential Refinements in a Mouse Bladder Cancer Model

“…Since the tumour model described by Betourne et al [58] should still have caused localised pain, another possible explanation of their negative findings could be that the mice were so incapacitated that they were insufficiently motivated make a chamber choice. However, other design differences could also offer an explanation.…”

“…These studies, and the results presented here show CPP testing is one of the very few methods with potential for effectively differentiating between the sensory (nociceptive) and affective dimensions of pain. We know of only one previous study where the CPP methodology has been used to assess cancer pain [58], and this failed to show CPP to morphine 24 days after development intra-plantar melanoma. Notably, they used a much higher morphine dose than in our study (10 mg/kg), so the lack of effects may have been due to tolerance issues or drug-induced hyperalgesia; both very common effects of repetitive opioid treatment.…”

CNS activation maps in awake rats exposed to thermal stimuli to the dorsum of the hindpaw

“…The islands of Calleja, which are interconnected with the amygdala (Fallon et al, 1978), displayed activation in response to pain. They are involved in morphine and cocaine reward modulation (Kornetsky et al, 1991) and have been shown to modulate the reward aspect of morphine in cancer and inflammatory pain (Betourne et al, 2008). Their specific role in processing acute pain it is not clear, however, their interconnection with other reward processing structures seems to indicate that they play a role in processing aversive/rewarding stimuli.…”

The application of conditioning paradigms in the measurement of pain

“…For example, morphine-induced conditioned place preference reportedly either did not change or was enhanced in complete Freund’s adjuvant-treated rats as compared to control rats in earlier reports (Shippenberg et al, 1988; Sufka, 1994). However, later studies have generally shown that morphine- or other opioid receptor agonists-induced conditioned place preference was decreased in animals with formalin-, carrageenan- or complete Freund’s adjuvant-induced inflammatory pain, sciatic nerve ligation-induced neuropathic pain or cancer pain in both rats and mice (Betourne et al, 2008; Nakamura et al, 2008; Narita et al, 2005; Niikura et al, 2008; Suzuki et al, 1996). More importantly, these behavioral results were supported by extensive pharmacological, neurochemical and biochemical studies (Niikura et al, 2010).…”

“…Another potential mechanism could be that the sustained release of the endogenous opioid peptide beta-endorphin leads to the dysfunction of μ opioid receptors in rats and mice with sciatic nerve ligation-induced neuropathic pain as both the knockout of beta-endorphin gene and the application of a specific beta-endorphin antibody eliminate pain-induced suppression of morphine conditioned place preference (Niikura et al, 2008). A third potential mechanism could be that the pain status enhances the central anti-opioid neuropeptides such as neuropeptide FF2 activity which subsequently suppresses morphine-induced place preference in animals with cancer pain or inflammatory pain (Betourne et al, 2008). Although it is unclear whether the different mechanisms are specific to the different animal models of pain and species, it is likely that more than one mechanism contributes to the decreased rewarding effects of morphine in these pain models.…”