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Negative affective states affect quality of life for patients suffering from pain. These maladaptive emotional states can lead to involuntary opioid overdose and many neuropsychiatric comorbidities. Uncovering the mechanisms responsible for pain-induced negative affect is critical in addressing these comorbid outcomes. The nucleus accumbens (NAc) shell, which integrates the aversive and rewarding valence of stimuli, exhibits plastic adaptations in the presence of pain. In discrete regions of the NAc, activation of the kappa opioid receptor (KOR) decreases the reinforcing properties of rewards and induces aversive behaviors. Using complementary techniques, we report that in vivo recruitment of NAc shell dynorphin neurons, acting through KOR, is necessary and sufficient to drive pain-induced negative affect. Taken together, our results provide evidence that pain-induced adaptations in the kappa opioid system within the NAc shell represent a functional target for therapeutic intervention that could circumvent pain-induced affective disorders. VIDEO ABSTRACT.

Key points Chronic treatment with opioids, such as morphine, leads to analgesic tolerance., While postsynaptic opioid tolerance is well documented, the involvement of presynaptic mechanisms remains unclear., We show that chronic morphine reduces the ability of periaqueductal grey (PAG) neurons to maintain GABAergic transmission., This depression of GABAergic transmission was due to a reduction in the effective size of the readily releasable pool., This also led to a reduction in opioid presynaptic inhibition; these presynaptic adaptations need to be considered in the development of strategies to reduce opioid tolerance., Abstract The midbrain periaqueductal grey (PAG) plays a critical role in tolerance to the analgesic actions of opioids such as morphine. While numerous studies have identified the postsynaptic adaptations induced by chronic morphine treatment in this and other brain regions, the presence of presynaptic adaptations remains uncertain. We examined GABAergic synaptic transmission within rat PAG brain slices from animals which underwent a low dose morphine treatment protocol which produces tolerance, but not withdrawal. Evoked GABAergic IPSCs (inhibitory postsynaptic currents) were less in morphine compared to control saline treated animals. Postsynaptic GABAA receptor mediated currents and desensitization, presynaptic release probability ( Pr), and inhibition by endogenous neurotransmitters were similar in morphine and saline treated animals. By contrast, the effective size of the readily releasable pool (RRP) was smaller in morphine treated animals. While the μ-opioid agonist DAMGO produced a reduction in Pr and RRP size in saline treated animals, it only reduced Pr in morphine treated animals. Consequently, DAMGO-induced inhibition of evoked IPSCs during short burst stimulation was less in morphine, compared to saline treated animals. These results indicate that low dose chronic morphine treatment reduces presynaptic μ-opioid inhibition by reducing the size of the pool of vesicles available for action potential dependent release. This novel presynaptic adaptation may provide important insights into the development of efficacious pain therapies that can circumvent the development of opioid tolerance. [ABSTRACT FROM AUTHOR]

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 tetrahydrocannabinol (THC) administered 12h 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 1day later. The primary objective of the present study was to test the hypothesis 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 2days enhanced the antinociceptive effect of HU-210 measured 1day later. In Experiment 2, twice daily systemic injections of THC enhanced the antinociceptive effect of morphine administered 1day 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. [Copyright &y& Elsevier]