The Roles And Mechanisms Of Dezocine On The Co-morbidity Of Pain And Itching

Objective At present, morphine is still most effective drugs for thetreatment of server pain. But it has serious adverse reactions, especially opioid-induced pruritus (OIP), which has greatly hampered the use of opioids as an analgesic. Consistently opioid antagonists, eg. naloxone, have been found to reduce itch.But it also can attenuate the analgesic effects. Usually, itch may be masked by pain which produced by scratch.However, in certain pathological conditions, pain maybe can enhance itch. Herpetic neuralgia is the disease that often pain and itching occur simultaneously. There is still no eeffective treatment. Dezocine is one of the newer mixed agonist-antagonist opioid analgesics. It is considered safer than pure agonist opioids, because of their ceiling effect for respiratory depression and their lower addiction potential.To observe the therapeutic efficacy of dezocine on the treatment for the co-morbidity of pain and itching.Methods All of the experiments were performed in accordance with the guidelines of Anhui Medical University Experimental Animal Ethics Committee. SPF male Kun-ming mice, weight (22-26) g were provided by the Experimental Animal Center of Anhui Medical University, weight (22-26) g, All of the behavioral tests were done by the observers blinded to the treatment of the animals.The first part of the experiment:Acute inflammatory pain and itching comorbid group. Adult male Kun-Ming mice (SPF grade,22-26g), were assigned randomly to nine groups (n=8):Group A (Control-NS-NS), Group B (Formalin-NS-NS), Group C (Formalin-NS-Dezocine), Group D (Formalin-Itch-NS), Group E (Control-Itch- NS), Group E (Formalin-Itch-Dezocine), Group F (Control-Itch-Dezocine), Group G(Formalin-Itch-Dezocine-Naloxone), Group H(Formalin-Itch-Dezocine-NS).To test pain threshold, lickig or flinching was recorded by video. Scratching behaviors of animals were video-recorded to analysis chloroquine-evoked itching in each group.The second part of the experiment:Chronic inflammatory pain and itching comorbid group. The mice were randomly divided into eight groups after acclimatization(n=8): Group A (Sham-NS-NS),Group B (CFA-NS-NS), Group C (Control-Itch-NS), Group D (CFA-Itch-NS), Group E (Control-Itch-Dezocine), Group F (CFA-Itch-Dezocine), Group G (CFA-Itch-Dezocine-NS), Group H (CFA-Itch-Dezocine-Naloxone). Mechanical allodynia was assessed by using electron-Von Frey. To test pain threshold, Paw withdrawal threshold (PWT, to assess mechanical allodynia) was measured by Electro VonFrey (IITC Life Science, USA) on-1d (baseline), Id,3d (before and after dezocine and chloroquine intradermal injection). For the hot plate test, the latency for the mice to lick its hindpaw or jump from the hotplate (52℃) was recorded. Scratching behaviors of animals were video-recorded, and the data was analyzed in each group.The third part of experiment:Chronic neuropathic pain and itching comorbid group. SPF grade,weight22-26g adult male Kun-Ming mice were assigned randomly to eight groups (n=8):Group A (Sham-NS-NS), Group B (SNI-NS-NS), Group C (Sham-Itch-NS), Group D (SNI-Itch-NS), Group E (Sham-Itch-Dezocine), Group F(SNI-Itch-Dezocine), Group G(SNI-Itch-Dezocine-NS), Group H(SNI-Itch-Dezocine-Naloxone). Mechanical sensitivity was assessed using electron-Von Frey. To test pain threshold, Paw withdrawal threshold (PWT, to assess mechanical allodynia) was measured by Electro VonFrey on-Id (baseline),1d,3d, and5d (before and after dezocine and chloroquine intradermal injection). Thermal sensitivity was determined by hot plate (52℃). The latency to withdrawal was measured. Itch behavioral tests were recorded by video to analysis chloroquine-evoked itching in each group.Statistical analysis:All data were expressed as the means±SD. Statistical comparisons were performed with two-way repeated measured analysis of variance (ANOVA) or Student’s t-test. p-value of<0.05was considered to be significant.Results The first part:Formalin (2%,20ul) injected subcutaneously into the hindpaw produced typical two-phase nociceptive behaviors, including flinching and licking of the injected hindpaw. Compared with group B, group C was significantly shorter time (P<0.05). Co-morbidity of itching and pain model of group F and group G, the number of scratching was less than group D and group E. The scratching latency was no statistically significance among co-morbidity of itching and pain model groups (P>0.05). Administrated antagonist naloxone, group H less than group I in scratching latency (P<0.05), and significant increased in the number of scratching (P<0.05).The second part:Complete Freund’s adjuvant induced chronic inflammatory pain model. Mechanical pain threshold and hot plate latency were significantly decreased (P <0.05). Compared with group C and group D, Group E and group F show significantly less time scratching and long time scratching latency (P<0.05). Injected naloxone, group G less than group H in scratching latency (P<0.05), and significant increased the number of scratching (P<0.05).The third part:PWT for mechanical allodynia or analgesic responses, group A<group B (P<0.05). Scratching latency in Group E or F of dezocine therapy are prolonged significantly compared to Group C or D (P<0.05). The number of scratching in Group C is significantly reduced compared to Group D. And the number of scratching in Group E or Group F is all reduced significantly compared to Group C or D (P<0.05). Administrated antagonist naloxone, group G less than group H in scratching latency (P <0.05) and group G significant increased the number of scratching compared to group H(P<0.05).ConclusionDezocine is a highly efficacious analgesics and well antipruritic treatment for the CPI in mice.