| Background:Pain is a complex physiological and psychological activity and is an unpleasant sensory and emotional experience associated with actual or potential tissue damage.As such it may alter the organism to physical damage or diseases.The long-lasting chronic pain does not have this beneficial effect;in contrast,it severely impairs quality of life.Numerous clinical studies have confirmed one-fifth of the world's population suffers from chronic pain,the most common of which is neuropathic pain.In 2011,International Association for the Study of Pain(IASP)defined neuropathic pain as pain induced by a direct lesion or disease to the somatosensory nervous system,typical symptoms of which are spontaneous pain,allodynia and hyperalgesia.Patients suffer from neuropathic pain always stay in a stress state and their normal activities are affected.The current various treatment strategies against neuropathic pain are quite limited and unmet clinical needs.One of the reasons is the insufficient mechanisms underlying neuropathic pain.Another contributing factor adversely influencing therapy is that patients affected by neuropathic pain are at high risk of being associated with disabilities,such as anxiety,depression,cognitive dificit and insomnia.A clinical study indicated that the prevalence of pain-mood disorders comorbidity is up to 47%.In addition to clinical researches,mounting animal models of neuropathic pain exhibit that pain and emotion interact with each other reciprocally.The underlying mechanisms contributing to the pain-affective disorders comorbidity,however,are not entirely understood.The endogenous cannabinoid system has a unique neuromodulatory effect in central nervous system.It consists of the endogenous ligands N-arachidonoylethanolamide(AEA),and 2-Arachidonoylglycerol(2-AG),the cannabinoid receptors(CB1R and CB2R)and the ligand synthesizing and degrading enzymes.Despite evidences supporting that the endogenous cannabinoid system plays a key role in nociceptive and affective processing,there are limited studies available identifying it in animal models of coexistence of mood changes and pain behavior.In this study,we try to explore the emotional changes in mice with neuropathic pain and the role of CB1R in it,providing new ideas for similar researches.Chronic constriction injury(CCI),as a stable animal pain model,has been widely used in pain research because it can mimic human conditions of neuropathic pain.Thus,we attempt to investigate whether mice suffer from CCI will be accompanied by mood complications and whether the CBiR mediates this process.Method:Neuropathic pain was induced by chronic constriction injury of the sciatic nerve in CB1 null(CB,R KO)mice and wild-type(WT)littermate controls.Mice were tested for allodynia and hyperalgesia at several time points:before operation,and on days 7,14,21,and 30 after the surgery.Tactile allodynia and thermal hyperalgesia were evaluated respectively by testing the mechanical withdrawal threshold and the thermal withdrawal latency.Then,mice were assessed by standard behavioral paradigms such as open field(OF),elevated plus-maze(EPM),sucrose preference(SP),and forced swimming(FS)for affective states 1 month after the surgery.Results:There were no differences observed in the mechanical and heat pain sensation among the mice with different genotype before the surgery.One week after the nerve ligation,we detected an increased tactile allodynia and thermal hyperalgesia in WT and CB1R KO animals in the hindpaw on the operated.So the pain model was well established as previously described.Moreover,compared with the mechanical withdrawal threshold,the duration of the reduction of thermal withdrawal latency lasted for 1 month longer.Interestingly,the heat hyperalgesia was observed in Sham CB1R KO mice on 21 days after surgery.In OF test,CBiR KO mice showed obvious anxiety behavior as spending less time in the center zone,while chronic pain did not alter behaviors in tests of locomotor activity and affective state.Likewise,in EPM test,no emotional changes were observed in mice after surgery,but there was interaction between genotype and gender on total frequency of entry into arms and time spent in the open arm.No effects were found in different genotype and operation mice in SP test.Finally,surgery and genotype had interaction on immobility time in FS test.Conclusions:1.Our study showed that sciatic nerve ligation can cause chronic pain in mice,coupled to a significant and stable decrease in the pain threshold,which can last for a month.2.The depression-like behavior was ameliorated after surgery in CB1R KO mice.3.CB1R KO mice exhibited increased susceptibility to the mood disorders like anxiety or depression;in addition,mice of different gender performed differently,that is male mice were more susceptible to anxiety-like behavior.Taken together,WT mice suffering from neuropathic pain do not have changes in any measure of affective state.The CB1R is related to modulate neuronal circuits contributing to affective behavior.The mechanisms by which the CB1R reverses the depression-like behavior of CB1R KO mice are not clear yet. |
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