| Background Chronic pain is a consequence of tissue injury,inflammatory,or tumor.It is physically and emothionally debilitating disorder for which the treatment is still far from perfect.Many patients respond poorly to conventional analdesics. Currently,the major classes of drugs recognized as being effective in chronic pain treatment are NSAIDs,antidepressants,anticonvulsants and opioids.However, systemic reviews reveal that only 30 to 50%of patients suffering from chronic pain achieve clinically significant(＞50%) pain relief with available single therapy.There remains a clear unmet medical need for drugs that provide greater efficacy/responder rates,which reduced side effects commonly experienced with current therapies.Complete Freund's adjunvant induce inflammatory nociception is a good animal model of inflammatory pain.This study characterized the manner in which ketamin or pregabalin interacts with morphine to suppress thermal hyperalgesia and mechanical allodynia in the rat model of complete Freund's adjunvant induced peripheral inflammation.Objective To study the antinociceptive synergy resulting from the combination of opioid receptor agonists,morphine,and N-methyl-D-aspartate(NMDA) receptor antagonists,ketamin,or anticonvulsant,pregabalin,on inflammatory pain.Methods Adult male Sprague-Dawley rats weithing 200-220 g were used in these experiments.Peripheral inflammatory nociception is induced by the intraplantar injection of the complete Freund's adjunvant(125μl).Rats in the control groups were injected with nomal saline(125μl).Rats in naive group received no interuption.Both paw withdrawal latencies(PWL,hot plate),and paw withdrawl threshold(PWT),electronic von Frey anesthesiometer were used to establish that animals were exhibiting allodynia and hyperalgesia.The antinociceptive effects of the opioid receptor agonist morphine(5,10 mg·kg-1,i.p.),NMDA receptor antagonist ketamine(10,20 mg·kg-1,i.p.),and anticonvulsant pregabalin(3,10,and 30 mg·kg-1, p.o.) were studied 72h after CFA injection,using the tactile and hot plat test. Coadministration of morphine with ketamine or morphine with pregabalin with the low dose were also performed and investigated.Every compound was used for 3 days. Nociceptive thresholds were examined at 15,30,60 and 120min post administration.Results Edema of the CFA injected paw was very significant during the first 5 days of inflammation.PWT and PWL were measured during the experimental days, and the findings revealed CFA injected rats exhibiting mechanical allodynia and thermal hyperalgesia(P＜0.01).Morphine induced a strong attenuation of mechanical allodynia and thermal hyperalgesia.Maximal anti-allodynic and antihyperalgesic efficacy was 95%and 88%(10 mg·kg-1),respectively,obtained on day 1,and they droped down to 50%and 22%,respectively on day 3.Even low dose of morphine(5 mg·kg-1) can attenuate the mechanical allodynia,but not thermal hyperalgesia. Morphine even shows some affection on nomal rats.When ketamin was administed alone,it shows effect neither on mechanical allodynia nor on thermal hyperalgesia. Pregabalin induced a weak to moderate attenuation of mechanical allodynia and thermal hyperalgesia.Maximal anti-allodynic and antihyperalgesic efficacy was 54% and 47%,respectively,both obtained at 10 mg·kg-1,the medium dose.No clear tolerance was found after repeated administration.It was found that both ketamine and pregabalin potentiated the antinociceptive effects of morphine,mainly on thermal hyperalgesia,58%and 63%respectively,P＜0.01.Still,after chronic treated for 3 days,it seemed no tolerance developed.Conclutions The present study offered a relatively broad pharmacological validation of the complete Freund's adjuvant induced peripheral inflammatory modal of chronic pain.Both ketamine and pregabalin potentiated the antinociceptive effects of morphine.
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