Zhang Anzhong, Pan Xiaopin, Xu Shaofen, Cheng Jieshi, Mo Huanying (Research Department of Acupuncture Analgesia, Shanghai First Medical College)
Since 1975, we have been studying the interrelationship between endorphins (including the endorphin fraction "29" which has been extracted by us from the human brain) and acupuncture analgesia.
Endorphin fraction "29"
Two fractions, "13" and "29", showing opioid activities in mouse vas deferens bioassay and opiate receptor binding assay, were extracted from the human brain. Fraction "13" was eluted from a Sephadex G-10 column in the void volume of 0.8-1.2, it was not inactivated by chymotrypsin. The Rf values of this fraction on thin layer plate chromatography conincided with that of leucine enkephalin. Basing on these results, fraction "13" might be an enkephalin or its related compound. Fraction "29" was eluted from the Sephadex G-10 column in the void volume of 1.8-2.4. It was readily inactivated by chymotrypsin, and its Rf values on thin layer plate chromatography were different from those of leucine enkephalin.
When it was dancylated with the dancyl-Cl and chromatographed on the polyamide layer sheet, its chromatogram of the fluorescent spots were different from the dancyl-leucine-enkephalin and dancyl-methionine-enkephalin. It showed a naloxone reversible analgesic effect in rabbits after intralateralventricular injection. Further purifying and structural analyzing studies of this endorphin fraction "29" is still going on.
The interrelationship between endorphins and acupuncture analgesia
I. Observations at the Presynaptic Level
(1) A statistically significant increase of endorphin in human CSF, and also a marked rise of the level of endorphin fraction "29" were observed during acupuncture analgesia.
(2) Using the techniques of push-pull perfusion and opiate receptor binding assay, we have observed continuously the release of endorphins in certain brain nuclei in conscious rabbits. It was found that the level of endorphins in the perfusate of central grey rose significantly during acupuncture analgesia, and the increment of endorphins correlated well with the analgesic effect of acupuncture (r=0.706, P<0.05). The release of endorphins also markedly increased in n. accumbens of the septal area after electro-acupuncture, but the increment did not correlate with the pain threshold. Similarly, endorphins in the perfusate of caudate nucleus also tended to increase during acupuncture analgesia, however, as the individual variation in this group was relatively large, there seemed to be of no statistic significance. No prominent changes of endorphin release in amygdala during acupuncture analgesia was observed.
The endorphin fraction which showed changes in amount during acupuncture were eluted prior to the sodium peak (0.6 Vt) when the perfusate were chromato-graphed on Sephadex G-10 column. Meanwhile, leucine-enkephalin was eluted behind the salt peak (1.3 Vt) thus suggesting that this endorphin fraction is not similar to enkephalin. Studies on the chemical properties of this fraction are still going on.
II. Observations at the Receptor Sites
(1) Naloxone antagonizes acupuncture analgesia
The inhibitory effects of acupuncture on responses both to somatic and visceral pain were partially, but significantly antagonized by naloxone or nalorphine (P<0.005, and P<0.025 respectively). This antagonism can be shown physiologically (cortical potentials evoked by tooth pulp stimulation, or impedence plethysmography etc.), biochemically (cAMP content in perfusate of caudate nucleus) and in behavior (potassium iontophoretic dolorimetry). Microinjections of naloxone and p-chloramphetamine into central grey have been carried out to study the role of this structure in acupuncture analgesia. The results indicated that the endorphin system and 5HT system in central grey play particular important roles in acupuncture analgesia.
We have also observed that the analgesic effect of "moderate strength electro-acupuncture" (with stimulating current of 7.5-8.0 mA, sufficient to elicit muscle twitching, but mild enough to keep the animals in quiet state) could be readily reversed by naloxone (0.4mg/kg i.v.); but the analgesic effect of "superstrength electro-acupuncture" (with stimulating current of 12.5-15 mA which made the animals struggle hard) could not. The analgesic potencies of these two kinds of electro-acupuncture were essentially similar, yet their responses to naloxone were markedly different, suggesting that analgesia produced by different strengths of electro-acupuncture are likely to occur from different mechanism. The further comparison between acupuncture analgesia and "stress analgesia" is in progress.
(2) Morphine analgesia does not cross tolerate with acupuncture analgesia
The acupuncture analgesic effect in morphine tolerant rabbits is similar with that in control animals. This analgesia could still be reversed by opiate antagonists such as levallorphan and naloxone.
Rabbits undergoing hours of continuous acupuncture showed a marked decrease of acupuncture analgesic effect, the pain threshold generally got back to pre-acupuncture level at 120th minute. At that time, morphine 5mg/kg intravenous injection elicited a marked increase of pain threshold, the analgesic potencies of morphine in these animals were similar with that in non-acupunctured animals.
The nonentity of cross tolerance between morphine analgesia and acupuncture analgesia suggests that the chronic pain patients having established tolerance to narcotic analgesics could still be treated with acupuncture to ease pain.
Our results show that the endorphin system takes part in acupuncture analgesia from presynaptic level to receptor sites. Among these, the mesencephalic central grey has attracted the most attention. Both the studies on release of endorphins and microinjections of antagonist indicate that the endorphin system is closely related with acupuncture analgesia. As central grey is also an important relay of the central pain pathway, it receives convergent but somatotopically organized somatosensory input, then inhibits the input of noxious stimuli in the dorsal horn of the spinal cord, via a descending inhibiting pathway. This negative feedback mechanism might be the main part of central analgesic mechanism. Acupunctural signals may get to central grey by way of somatosensory input path, thus activating the central analgesic mechanism.
However, the functions of endorphins are far more than just analgesia, and the central analgesic system does not consist only of endorphins, Since acupuncture analgesia is a comprehensive result of multifactors, further studies must be made on the interactions between endorphins and the non-endorphin components and other neurotransmitters in the mechanism of acupuncture analgesia.
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