Han Jisheng (Research Group of Acupuncture Anesthesia, Beijing Medical College)
Studies were made to evaluate the role played by some central neurotransmitters in acupuncture analgesia (AA). Experiments were programmed along two parallel and reciprocal lines: (1) Does acupuncture bring about any change in the content or turnover rate of the central neurotransmitters? (2) Could the effect of AA be affected by selective alteration of the functional status of certain central neurotransmitters?
Most of the experiments were performed on rabbits and rats using radiant heat antinociceptive test for assessment of the effect of AA. Among many putative neurotransmitters we paid special attention to four of them: serotonin (5-HT), acetylcholine (ACh), catecholamines (CAs), including norepinephrine (NE) and dopamine (DA) and the endogenous opiate-like substances (OLS), which were known to be implicated in pain and analgesia.
Central Serotonin
1. Effect of lowering 5-HT content on AA: Blockade of 5-HT synthesis by PCPA in rabbits and rats or chemical denervation of the ascending 5-HT fibers by 5,6-DHT in rats brought about significant decrease of the effect of AA.
2. Effect of elevating 5-HT activity on AA: The effect of AA in rats was significantly augmented by the intraperitoneal (ip) or intraventricular (ivt) injection of 5-HTP, the immediate precursor of 5-HT, which raised the cerebral 5-HT content by more than 100%. In a clinical double blind study the effect of acupuncture anesthesia for extraction of the last molar was significantly strenghthened by the prior oral administration of clomipramine which blocked the reuptake of 5-HT and thus raised its functional activity.
3. Effect of acupuncture on the activity of central 5-HT neurons: Acupuncture raised the 5-HT content in rat brain significantly. Turnover study revealed that both synthesis and utilization of central 5-HT were accelerated during acupuncture. As the rate of the former exceeded that of the latter, more 5-HT accumulated. In accordance with this were the results of the electrophysiological study in rats which indicated that the rate of unit discharge of dorsal raphe nucleus was significantly increased during and within 10 minutes after the ceasation of electroacupuncture.
The above mentioned results suggest that serotonin in CNS is an important substrate for the mediation of AA.
Central Acetylcholine
1. Blockade of ACh synthesis by the ivt injection of hemicholine (HC-3) in rats impeded the effect of AA which was partially reversed by ip administration of choline chloride, the precursor of ACh. The effect of AA in rabbits and rats could likewise be partially blocked by atropine, the antagonist of the muscarinic ACh receptors.
2. Eserine which potentiated the activity of endogenously released ACh augmented AA in rats.
The results suggest that central ACh might also take part in mediating AA.
Central Catecholamines
1. Effect of DA: Ivt injection of apomorphine, the agonist of DA receptor, attenuated AA in rabbits. Administration of droperidol, the antagonist for DA receptor, potentiated the effect of AA not only in animal experiments but also in humans operated upon for thyroidectomy under acupuncture anesthesia.
2. The à-effect of NE: The effect of AA in rats was partially blocked by ivt injection of DOPS, the precursor of NE, or the administration of clonidine, the agonist for central à-receptors, and significantly augmented by phentolamine, the antagonist for à-receptors or intracerebral injection of 6-OHDA which destroyed the ascending NE fibers to the forebrain. Microinjection study revealed that habenula was one of the important areas where à-receptors exerted their blocking effect on AA. Injection of clonidine or phentolamine into amygdala was ineffective in this regard.
From the above mentioned results it follows that DA (through DA receptor) and NE (through its à-receptor) in CNS may exert an antagonistic effect on AA.
3. á-Effect: The attenuating effect of DOPS on AA could be reversed by phentolamine, the 224-blocker, but not by propranolol, the á-blocker. Propranolol per se (ip or ivt) caused a decrease in the effect of AA in rats, which was in line with the clinical finding that propranolol made the acupuncture anesthesia less effective than the control group, indicating a facilitating effect of á-receptor in AA.
That the overall effect of increase of cerebral NE (by DOPS) was to lower the effectiveness of AA suggested that of these two contradicting effects, à-effect seemed to be the one that predominated.
4. Effect of acupuncture on the activity of NE neurones: Electroacupuncture caused a significant lowering of cerebral NE content which was found by turnover studies to be the result of a greater rate of utilization than that of synthesis in the brain.
Endogenous Opiate-like Substances (OLS) and Anti-opiate Substances (AOS)
1. Effect of acupuncture on OLS activity: The elevation of pain threshold in rats after electroacupuncture was accompanied by an elevation of OLS activity (measured by radioreceptor assay) in whole brain and certain brain areas, among them the telencephalon (notably the septum-accumbens) and the mesencephalon seemed to be most intimately implicated. In normal human volunteers the blood level of OLS was found to be positively correlated with the effect of AA.
2. Effect of blocking opiate receptors on AA: Injection of naloxone, the opiate antagonist, into the lateral ventricle of the rabbit or bilateral discrete brain areas in rabbits (habenula, accumbens, amygdala) or rats (habenula or accumbens) significantly decrease the effect of AA.
3. Interrelationship between OLS and 5-HT: While a reduction of cerebral 5-HT content in rats after injection of PCPA or 5,6-DHT was accompanied by a marked elevation of the OLS activity, blockade of opiate receptors by ivt injection of naloxone was accompanied by an elevation in the cerebral 5-HT content, implying a compensatory interrelation between these two neurochemical agents. Since the effect of AA (Y) was well correlated with the content of 5-HT (X[1]) as well as that of OLS (X[2]), the relation between these 3 factors could be summarized in a regression equation Y=0.61X[1]0.48X[2]-62 (p<0.001). Thus the individual variation of the effect of AA seen in animals and humans might be partially accounted for by the differences in reactivity of these two neurochemical systems to the acupuncture stimulus.
4. Acupuncture tolerance: Prolonged electroacupuncture in rats resulted in a gradual decrease in its analgesic effect, implying the development of tolerance to acupuncture. Rats exhibited tolerance to acupuncture which might be concerned with tolerance to "endogenous morphine", showed a tolerance to exogenous morphine (6mg/kg, sc) as well. The brains of the acupuncture-tolerant rats were extracted for the possible existence of an endogenous anti-opiate substance, using the method adopted by Ungar. Ivt injection of the brain extract to normal rats revealed an antagonistic activity not only to AA but also to morphine analgesia. The chemical nature and its possible physiological significance remained to be studied.
5. The role of cyclic nucleotides: Ivt injection of cAMP in rats lowered the effect of morphine analgesia as well as AA; injection of cGMP, on the contrary, potentiated AA. The roles played by cyclic nucleotides, which were implicated not only in morphine and OLS but also in many other neurotransmitters, are worthy of further study.
SUMMARY: Following the application of acupuncture, different kinds of neurons in the CNS were activated and different kinds of neurotransmitters released. Some of the neurotransmitters (5-HT, ACh, OLS, NE-á) facilitated AA, while others (DA, NE-à, AOS) attenuated it. The effectiveness of AA was the result of complex interaction of and delicate balance between these neurochemicals, among them 5-HT and OLS seemed to be the key links.
Studies were made to evaluate the role played by some central neurotransmitters in acupuncture analgesia (AA). Experiments were programmed along two parallel and reciprocal lines: (1) Does acupuncture bring about any change in the content or turnover rate of the central neurotransmitters? (2) Could the effect of AA be affected by selective alteration of the functional status of certain central neurotransmitters?
Most of the experiments were performed on rabbits and rats using radiant heat antinociceptive test for assessment of the effect of AA. Among many putative neurotransmitters we paid special attention to four of them: serotonin (5-HT), acetylcholine (ACh), catecholamines (CAs), including norepinephrine (NE) and dopamine (DA) and the endogenous opiate-like substances (OLS), which were known to be implicated in pain and analgesia.
Central Serotonin
1. Effect of lowering 5-HT content on AA: Blockade of 5-HT synthesis by PCPA in rabbits and rats or chemical denervation of the ascending 5-HT fibers by 5,6-DHT in rats brought about significant decrease of the effect of AA.
2. Effect of elevating 5-HT activity on AA: The effect of AA in rats was significantly augmented by the intraperitoneal (ip) or intraventricular (ivt) injection of 5-HTP, the immediate precursor of 5-HT, which raised the cerebral 5-HT content by more than 100%. In a clinical double blind study the effect of acupuncture anesthesia for extraction of the last molar was significantly strenghthened by the prior oral administration of clomipramine which blocked the reuptake of 5-HT and thus raised its functional activity.
3. Effect of acupuncture on the activity of central 5-HT neurons: Acupuncture raised the 5-HT content in rat brain significantly. Turnover study revealed that both synthesis and utilization of central 5-HT were accelerated during acupuncture. As the rate of the former exceeded that of the latter, more 5-HT accumulated. In accordance with this were the results of the electrophysiological study in rats which indicated that the rate of unit discharge of dorsal raphe nucleus was significantly increased during and within 10 minutes after the ceasation of electroacupuncture.
The above mentioned results suggest that serotonin in CNS is an important substrate for the mediation of AA.
Central Acetylcholine
1. Blockade of ACh synthesis by the ivt injection of hemicholine (HC-3) in rats impeded the effect of AA which was partially reversed by ip administration of choline chloride, the precursor of ACh. The effect of AA in rabbits and rats could likewise be partially blocked by atropine, the antagonist of the muscarinic ACh receptors.
2. Eserine which potentiated the activity of endogenously released ACh augmented AA in rats.
The results suggest that central ACh might also take part in mediating AA.
Central Catecholamines
1. Effect of DA: Ivt injection of apomorphine, the agonist of DA receptor, attenuated AA in rabbits. Administration of droperidol, the antagonist for DA receptor, potentiated the effect of AA not only in animal experiments but also in humans operated upon for thyroidectomy under acupuncture anesthesia.
2. The à-effect of NE: The effect of AA in rats was partially blocked by ivt injection of DOPS, the precursor of NE, or the administration of clonidine, the agonist for central à-receptors, and significantly augmented by phentolamine, the antagonist for à-receptors or intracerebral injection of 6-OHDA which destroyed the ascending NE fibers to the forebrain. Microinjection study revealed that habenula was one of the important areas where à-receptors exerted their blocking effect on AA. Injection of clonidine or phentolamine into amygdala was ineffective in this regard.
From the above mentioned results it follows that DA (through DA receptor) and NE (through its à-receptor) in CNS may exert an antagonistic effect on AA.
3. á-Effect: The attenuating effect of DOPS on AA could be reversed by phentolamine, the 224-blocker, but not by propranolol, the á-blocker. Propranolol per se (ip or ivt) caused a decrease in the effect of AA in rats, which was in line with the clinical finding that propranolol made the acupuncture anesthesia less effective than the control group, indicating a facilitating effect of á-receptor in AA.
That the overall effect of increase of cerebral NE (by DOPS) was to lower the effectiveness of AA suggested that of these two contradicting effects, à-effect seemed to be the one that predominated.
4. Effect of acupuncture on the activity of NE neurones: Electroacupuncture caused a significant lowering of cerebral NE content which was found by turnover studies to be the result of a greater rate of utilization than that of synthesis in the brain.
Endogenous Opiate-like Substances (OLS) and Anti-opiate Substances (AOS)
1. Effect of acupuncture on OLS activity: The elevation of pain threshold in rats after electroacupuncture was accompanied by an elevation of OLS activity (measured by radioreceptor assay) in whole brain and certain brain areas, among them the telencephalon (notably the septum-accumbens) and the mesencephalon seemed to be most intimately implicated. In normal human volunteers the blood level of OLS was found to be positively correlated with the effect of AA.
2. Effect of blocking opiate receptors on AA: Injection of naloxone, the opiate antagonist, into the lateral ventricle of the rabbit or bilateral discrete brain areas in rabbits (habenula, accumbens, amygdala) or rats (habenula or accumbens) significantly decrease the effect of AA.
3. Interrelationship between OLS and 5-HT: While a reduction of cerebral 5-HT content in rats after injection of PCPA or 5,6-DHT was accompanied by a marked elevation of the OLS activity, blockade of opiate receptors by ivt injection of naloxone was accompanied by an elevation in the cerebral 5-HT content, implying a compensatory interrelation between these two neurochemical agents. Since the effect of AA (Y) was well correlated with the content of 5-HT (X[1]) as well as that of OLS (X[2]), the relation between these 3 factors could be summarized in a regression equation Y=0.61X[1]0.48X[2]-62 (p<0.001). Thus the individual variation of the effect of AA seen in animals and humans might be partially accounted for by the differences in reactivity of these two neurochemical systems to the acupuncture stimulus.
4. Acupuncture tolerance: Prolonged electroacupuncture in rats resulted in a gradual decrease in its analgesic effect, implying the development of tolerance to acupuncture. Rats exhibited tolerance to acupuncture which might be concerned with tolerance to "endogenous morphine", showed a tolerance to exogenous morphine (6mg/kg, sc) as well. The brains of the acupuncture-tolerant rats were extracted for the possible existence of an endogenous anti-opiate substance, using the method adopted by Ungar. Ivt injection of the brain extract to normal rats revealed an antagonistic activity not only to AA but also to morphine analgesia. The chemical nature and its possible physiological significance remained to be studied.
5. The role of cyclic nucleotides: Ivt injection of cAMP in rats lowered the effect of morphine analgesia as well as AA; injection of cGMP, on the contrary, potentiated AA. The roles played by cyclic nucleotides, which were implicated not only in morphine and OLS but also in many other neurotransmitters, are worthy of further study.
SUMMARY: Following the application of acupuncture, different kinds of neurons in the CNS were activated and different kinds of neurotransmitters released. Some of the neurotransmitters (5-HT, ACh, OLS, NE-á) facilitated AA, while others (DA, NE-à, AOS) attenuated it. The effectiveness of AA was the result of complex interaction of and delicate balance between these neurochemicals, among them 5-HT and OLS seemed to be the key links.
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