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It has been reported by Stein et al. that the immune system and peripheral opioid receptors are involved in the control of pain accompanying inflammation. Electroacupuncture (EA) is used to relieve various kinds of pain. However, little is known about the effect of electroacupuncture analgesia (EAA) during hyperalgesia elicited by inflammation. The aim of the present study was to compare (1) the individual variation of EAA, (2) the durability of EAA, and (3) the effect of naloxone on EAA between normal rats and rats subjected to acute inflammatory pain. Carrageenan was subcutaneously administered by intraplantar (i.pl.) injection of the left hind paw to induce a nociceptive response. Nociceptive thresholds were measured using the paw pressure threshold (PPT). Rats received EA at 3 Hz in the left anterior tibial muscles for 1 hour after carrageenan injection. Naloxone was administered by intraperitoneal (i.p.) or i.pl. injection just before EA. EAA was elicited in 15 of 29 normal rats. These rats were divided into responders and non-responders. EAA in the responder group was almost completely antagonized by i.p. injection of naloxone. In contrast, in all the rats with carrageenan-induced inflammation, EAA was elicited, lasted for at least 24 hours after carrageenan injection, and was dose-dependently antagonized by i.pl. injection, but not significantly by i.p. injection of naloxone. It seems likely that the EAA in the rats with carrageenan-induced inflammation differs from that in normal rats, and these findings suggest that peripheral opioid receptors are involved in EAA during inflammatory conditions.

Electroacupuncture (EA) is used to relieve various kinds of pain. However, the mechanistic basis of electroacupuncture analgesia (EAA) in inflammatory pain remains unclear. In the present study, we investigated whether endogenous peripheral corticotropin-releasing factor (CRF) or interleukin-1β (IL-1) participated in EAA during hyperalgesia elicited by carrageenan-induced inflammation. Carrageenan was subcutaneously administered by intraplantar (i.pl.) injection of the left hind paw to induce inflammation. Nociceptive thresholds were measured using the paw pressure threshold (PPT) (Randall Sellito Test). Rats received 3 Hz EA in the left anterior tibial muscles for 1 hour after carrageenan injection. The selective CRF antagonist, α-helical CRF, or the recombinant IL-1 receptor antagonist, IL-1ra, was administered by i.pl. injection of the inflamed paw or by intravenous (i.v.) injection 1 hour before EA. PPT decreased significantly 3 hours after carrageenan injection. This decrease persisted at least 24 hours after carrageenan injection. EA resulted in significant increases of PPT, moreover, PPT elevations lasted 24 hours after carrageenan injection. By contrast, PPT elevations produced by EA were dose-dependently antagonized by local i.pl. injection of α-helical CRF or IL-1ra. This PPT elevation was not influenced by i.v. injection of α-helical CRF or IL-1ra. These findings suggest that peripheral CRF or IL-1 participate in EAA during hyperalgesia. The release of CRF or IL-1 elicited by EA may trigger the release of opioid peptides within inflamed tissue which may activate peripheral opioid receptors and inhibit the pain.

Chinese herbal medicine has been used for thousands of years in China and other Asian countries to treat a variety of inflammatory diseases. The classic Chinese herbal formula, Huo Luo Xiao Ling Dan (活络效灵丹, HLXL) is commonly used in traditional Chinese herbal medicine for the treatment of joint pain and other symptoms of arthritis. The present study is an investigation of the effects of a modified HLXL extract on persistent hyperalgesia and edema in rats with peripheral inflammation. Inflammation was induced by injecting complete Freund's adjuvant (CFA) into one hind paw. Four dosages of the extract were compared to a vehicle control. Each was administered intragastrally (i.g.) daily for seven days beginning one day before CFA. Hyperalgesia was assessed using a paw withdrawal latency (PWL) test and edema was determined by measuring paw thickness at pre-CFA and 2 hours, 24 hours, and 5 days post-CFA. Immunohistochemistry was performed 2 hours post-CFA to determine spinal Fos protein expression. Adverse effects of the extract were monitored by observing the animals closely for unusual behavioral changes. Compared to the control, HLXL at the two lower dosages (0.575 g/kg and 1.15 g/kg) were effective in the later stage (day 5) of inflammatory hyperalgesia and edema, while the two higher dosages (2.3 g/kg and 4.6 g/kg) alleviated early stage hind paw inflammation and hyperalgesia and facilitated recovery from paw edema and hyperalgesia during the late stage. HLXL at 2.30 g/kg significantly suppressed Fos expression in laminae I–II, III–IV and V–VI ipsilaterally and in III-IV contralaterally. No significant signs of toxicity or adverse effects were observed. The data suggest that HLXL dosage-dependently attenuates CFA-induced inflammation and hyperalgesia, at least in part by inhibiting noxious transmission at the dorsal horn of the spinal cord.

We investigated the anti-inflammatory effects of electroacupuncture (EA) on carrageenan-induced inflammatory model in association with peripheral and spinal COX-2 expression. EA with 2, 15 and 120 Hz, especially 2 Hz, had significant inhibitory effects on the developing of edema and hyperalgesia, which was measured in 30-min intervals after carrageenan injection. Therefore, we investigated whether the effect of 2 Hz EA on carrageenan-induced edema and hyperalgesia is associated with peripheral and spinal expression of inflammatory proteins. The expression of cyclooxygenase (COX)-1, COX-2, and inducible nitric oxide synthase (iNOS) was inhibited by 2 Hz EA in carrageenan-injected rat paws. Interestingly, we found that the mRNA of COX-1 and COX-2 expression in the spine was not induced by 2 Hz EA treatment after carrageenan-induced peripheral inflammation. In addition, synthesis of prostaglandin E₂ (PGE₂) was partially inhibited by 2 Hz EA treatment in both peripheral and spinal nociceptive regions. In conclusion, EA treatment might be a useful therapy for mitigation of inflammatory edema and hyperalgesia through regulation of COX-2 expression in both peripheral and central nociceptive sites.