Role of the endocannabinoid system in the emotional manifestations of osteoarthritis pain.

In this study, we investigated the role of the endocannabinoid system (ECS) in the emotional and cognitive alterations associated with osteoarthritis pain. The monosodium iodoacetate model was used to evaluate the affective and cognitive manifestations of osteoarthritis pain in type 1 (CB1R) and type 2 (CB2R) cannabinoid receptor knockout and wild-type mice and the ability of CB1R (ACEA) and CB2R (JWH133) selective agonists to improve these manifestations during a 3-week time period. The levels of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured in plasma and brain areas involved in the control of these manifestations. Patients with knee osteoarthritis and healthy controls were recruited to evaluate pain, affective, and cognitive symptoms, as well as plasma endocannabinoid levels and cannabinoid receptor gene expression in peripheral blood lymphocytes. The affective manifestations of osteoarthritis were enhanced in CB1R knockout mice and absent in CB2R knockouts. Interestingly, both ACEA and JWH133 ameliorated the nociceptive and affective alterations, whereas ACEA also improved the associated memory impairment. An increase of 2-AG levels in prefrontal cortex and plasma was observed in this mouse model of osteoarthritis. In agreement, an increase of 2-AG plasmatic levels and an upregulation of CB1R and CB2R gene expression in peripheral blood lymphocytes were observed in patients with osteoarthritis compared with healthy subjects. Changes found in these biomarkers of the ECS correlated with pain, affective, and cognitive symptoms in these patients. The ECS plays a crucial role in osteoarthritis and represents an interesting pharmacological target and biomarker of this disease.

Influence of δ-opioid receptors in the behavioral effects of nicotine.

Multiple studies in animal models and humans suggest that the endogenous opioid system is an important neurobiological substrate for nicotine addictive properties. In this study, we evaluated the participation of δ-opioid receptors in different behavioral responses of nicotine by using δ-opioid receptor knockout mice. Acute nicotine administration induced hypolocomotion and antinociception in wild-type mice, which were similar in knockout animals. The development of tolerance to nicotine-induced antinociception was also similar in both genotypes. In agreement, the expression and functional activity of δ-opioid receptors were not modified in the different layers of the spinal cord and brain areas evaluated after chronic nicotine treatment. The somatic manifestation of the nicotine withdrawal syndrome precipitated by mecamylamine was also similar in wild-type and δ-opioid receptor knockout mice. In contrast, nicotine induced a conditioned place preference in wild-type animals that was abolished in knockout mice. Moreover, a lower percentage of acquisition of intravenous nicotine self-administration was observed in mice lacking δ-opioid receptors as well as in wild-type mice treated with the selective δ-opioid receptor antagonist naltrindole. Accordingly, in-vivo microdialysis studies revealed that the enhancement in dopamine extracellular levels induced by nicotine in the nucleus accumbens was reduced in mutant mice. In summary, the present results show that δ-opioid receptors are involved in the modulation of nicotine rewarding effects. However, this opioid receptor does not participate either in several acute effects of nicotine or in the development of tolerance and physical dependence induced by chronic nicotine administration.

Effects of chronic nicotine on food intake and anxiety-like behaviour in CB(1) knockout mice.

We have evaluated the effects of chronic nicotine administration and withdrawal in food intake and preference, metabolic parameters and anxiety-like behaviour in CB(1) knockout mice and wild-type littermates. Mutant mice showed lower levels of glucose, insulin and cholesterol after two weeks of high fat diet and reduced preference for saccharin solution when compared with wild-type mice. Nicotine reduced body weight and induced anxiogenic-like effects in wild-type, but not in CB(1) knockout mice. Our results suggest a modulatory role of the endocannabinoid system on the effects induced by nicotine on metabolic parameters and anxiety-like responses.

Prodynorphin gene disruption increases the sensitivity to nicotine self-administration in mice.

The endogenous opioid system has been reported to participate in nicotine behavioural responses. The aim of the study was to determine the contribution of the endogenous peptides derived from prodynorphin in acute and chronic nicotine responses, mainly those related to its addictive properties. Locomotion and nociception were evaluated after acute nicotine administration in prodynorphin knockout mice. In addition, nicotine rewarding properties were investigated in the place-conditioning and the intravenous self-administration paradigms. The somatic signs of nicotine withdrawal were also analysed after the injection of the nicotinic antagonist mecamylamine in nicotine-dependent mice. The hypolocomotor and antinociceptive effects induced by acute nicotine administration were not modified in knockout (KO) animals. Nicotine also produced similar conditioned place preference in both genotypes. However, a shift to the left in the percentage of acquisition of intravenous nicotine-self administration was observed in prodynorphin KO mice. Indeed, a significant increase in the number of KO mice acquiring this operant behaviour was revealed when low doses of nicotine were used. Nicotine physical dependence was similar in wild-type and KO animals. These findings reveal a specific role of endogenous peptides derived from prodynorphin in nicotine self-administration, probably through the modulation of its aversive effects.