Physiology & Behavior, Vol. 52, pp. 405-410, 1992
0031-9384/92 $5.00 + .00 Copyright © 1992 Pergamon Press Ltd.
Printed in the USA.
Opioid Mediation of the Antiaversive and Hyperalgesic Actions of Bradykinin Injected Into the Dorsal Periaqueductal Gray of the Rat T. A. B U R D I N , * F. G. G R A E F F t A N D I. R. P E L A .1
*Laboratory of Pharmacology, F.C.F.R.P., and ?Laboratory of Psychobiology, F.F.C.LR.P., University of S~o Paulo, Campus of Ribeirdo Preto, 14.049 Ribeir~o Preto, SP, Brazil Received 20 J u n e 1991 BURDIN, T. A., F. G. GRAEFF AND I. R. PELA. Opioidmediation of the antiaversiveand hyperalgesicactions ofbradykinin injected into the dorsalperiaqueductalgray of the rat. PHYSIOL BEHAV 52(3) 405-410, 1992.--Reported evidence indicates that the dorsal region of the periaqueductal gray matter (PAG) is involved in the modulation of both pain and aversion, and that opioid mechanisms, among others, participate in their modulation. Since many central actions of bradykinin (BK) have been shown to be similar to those of morphine, the present was undertaken to measure the effects of microinjection of BK into the PAG on the thresholds of aversiveelectricalstimulation of the same brain area and of dental pulp electricalstimulation. Bradykinin, injected into the dorsal PAG, induced a dose-dependent increase in the aversive threshold, an effect similar to that reported by others for morphine. Also, as reported for morphine, the antiaversive effect of BK was antagonized by naloxone injected intraperitoneally.Whereas subcutaneouslyadministered morphine induced marked analgesia,intra-PAG administration of BK caused a small but significant hyperalgesia. Similarly, morphine injected into the dorsal PAG tended to cause hyperalgesia instead of analgesia. Furthermore, the hyperalgesiceffect of BK also appears to involve opioid mechanisms since it was blocked by naloxone. As in previously reported studies, intracerebroventricularlyinjected BK raised the pain threshold. These results indicate that BK mobilizes opioid mechanisms in the dorsal PAG that inhibit aversion but not pain. Bradykinin
Dorsalperiaqueductal gray
Aversion
Nociception
Naloxone
Rat
behavior or defensive aggression in rats and cats (14,33), together with autonomic changes (40) that have been associated either with pain or fear (26,33). With regard to the neurohumoral mechanisms that participate in the modulation of aversion and defense in the dorsal PAG, experimental evidence reported thus far points to a major influence of GABAergic and serotoninergic neurotransmission (4,40,43). Nevertheless, opioid mechanisms may also play an important modulatory role in this brain area, since microinjection of morphine into the dorsal PAG of the rat attenuated both the behavioral and autonomic consequences of its electrical stimulation, and such effects were antagonized by naloxone (4,23,24). In the present study, the effects of BK microinjected into the dorsal PAG of the rat on flight behavior induced by PAG electrical stimulation (4), as well as on the jaw-opening reflex elicited by nociceptive electrical stimulation of the dental pulp, were measured. As a next step, the influence of naloxone pretreatment on the effects of BK was assessed. Because conflicting results on the effect of morphine injected into the dorsal PAG on nociception have been reported (6,24), the effect of such injection on the jaw-opening reflex was also measured. The antinociceptive
THERE are several similarities between the central actions of morphine and those of the nonapeptide bradykinin (BK) belonging to the kinin family (38). Intraventricular or intracerebral administration of either BK or morphine has been shown to cause central monoamine depletion (7,16), hyperglycemia (3,35), hyperthermia (1,2), stereotypical behavior (7,15,16), sedation, and catatonia (12,15,16) and antinociceptive effects in rats or rabbits (7,29,30). Therefore, it is possible that BK influences opioid mechanisms in the periaqueductal gray matter (PAG). The identification of endogenous BK in the central nervous system, together with enzyme systems for the synthesis and degradation of the polypeptide (8,11,34), support the early suggestion that BK may be a neurotransmitter in the CNS (17). In addition, immunohistochemical studies have localized neuronal cell bodies containing BK in the hypothalamus, mainly inside the paraventricular and dorsomedial nuclei, while nerve fibers and varicosities have been found in several other structures, including the PAG (11,25,34)., In contrast to the participation of the ventral PAG in the modulation of pain (14,46), many studies implicate the dorsal PAG in the control of defensive behavior and aversion (13). Thus, electrical stimulation of the dorsal PAG induces flight
Requests for reprints should be addressed to I. R. Pelfi, Laborat6rio de Farmacologia, Faculdade de Ci~ncias Farmac~uticas, Ribeir~o Preto, USP, Campus Universifftrio,14049 Ribeirao Preto, Sao Paulo, Brasil. 405
406
B U R D I N , G R A E F F A N D PELA
to Corraa and Graeff (6). The cannulas was fixed to the skull with two steel screws and dental cement and kept patent with a sterile obturator. After receiving a penicillin combination, IM, the animals were housed individually and allowed to recover for at least 1 week before the experiments.
,Jr
o3 12,
Procedures
0031-9384/92 $5.00 + .00 Copyright © 1992 Pergamon Press Ltd.
Printed in the USA.
Opioid Mediation of the Antiaversive and Hyperalgesic Actions of Bradykinin Injected Into the Dorsal Periaqueductal Gray of the Rat T. A. B U R D I N , * F. G. G R A E F F t A N D I. R. P E L A .1
*Laboratory of Pharmacology, F.C.F.R.P., and ?Laboratory of Psychobiology, F.F.C.LR.P., University of S~o Paulo, Campus of Ribeirdo Preto, 14.049 Ribeir~o Preto, SP, Brazil Received 20 J u n e 1991 BURDIN, T. A., F. G. GRAEFF AND I. R. PELA. Opioidmediation of the antiaversiveand hyperalgesicactions ofbradykinin injected into the dorsalperiaqueductalgray of the rat. PHYSIOL BEHAV 52(3) 405-410, 1992.--Reported evidence indicates that the dorsal region of the periaqueductal gray matter (PAG) is involved in the modulation of both pain and aversion, and that opioid mechanisms, among others, participate in their modulation. Since many central actions of bradykinin (BK) have been shown to be similar to those of morphine, the present was undertaken to measure the effects of microinjection of BK into the PAG on the thresholds of aversiveelectricalstimulation of the same brain area and of dental pulp electricalstimulation. Bradykinin, injected into the dorsal PAG, induced a dose-dependent increase in the aversive threshold, an effect similar to that reported by others for morphine. Also, as reported for morphine, the antiaversive effect of BK was antagonized by naloxone injected intraperitoneally.Whereas subcutaneouslyadministered morphine induced marked analgesia,intra-PAG administration of BK caused a small but significant hyperalgesia. Similarly, morphine injected into the dorsal PAG tended to cause hyperalgesia instead of analgesia. Furthermore, the hyperalgesiceffect of BK also appears to involve opioid mechanisms since it was blocked by naloxone. As in previously reported studies, intracerebroventricularlyinjected BK raised the pain threshold. These results indicate that BK mobilizes opioid mechanisms in the dorsal PAG that inhibit aversion but not pain. Bradykinin
Dorsalperiaqueductal gray
Aversion
Nociception
Naloxone
Rat
behavior or defensive aggression in rats and cats (14,33), together with autonomic changes (40) that have been associated either with pain or fear (26,33). With regard to the neurohumoral mechanisms that participate in the modulation of aversion and defense in the dorsal PAG, experimental evidence reported thus far points to a major influence of GABAergic and serotoninergic neurotransmission (4,40,43). Nevertheless, opioid mechanisms may also play an important modulatory role in this brain area, since microinjection of morphine into the dorsal PAG of the rat attenuated both the behavioral and autonomic consequences of its electrical stimulation, and such effects were antagonized by naloxone (4,23,24). In the present study, the effects of BK microinjected into the dorsal PAG of the rat on flight behavior induced by PAG electrical stimulation (4), as well as on the jaw-opening reflex elicited by nociceptive electrical stimulation of the dental pulp, were measured. As a next step, the influence of naloxone pretreatment on the effects of BK was assessed. Because conflicting results on the effect of morphine injected into the dorsal PAG on nociception have been reported (6,24), the effect of such injection on the jaw-opening reflex was also measured. The antinociceptive
THERE are several similarities between the central actions of morphine and those of the nonapeptide bradykinin (BK) belonging to the kinin family (38). Intraventricular or intracerebral administration of either BK or morphine has been shown to cause central monoamine depletion (7,16), hyperglycemia (3,35), hyperthermia (1,2), stereotypical behavior (7,15,16), sedation, and catatonia (12,15,16) and antinociceptive effects in rats or rabbits (7,29,30). Therefore, it is possible that BK influences opioid mechanisms in the periaqueductal gray matter (PAG). The identification of endogenous BK in the central nervous system, together with enzyme systems for the synthesis and degradation of the polypeptide (8,11,34), support the early suggestion that BK may be a neurotransmitter in the CNS (17). In addition, immunohistochemical studies have localized neuronal cell bodies containing BK in the hypothalamus, mainly inside the paraventricular and dorsomedial nuclei, while nerve fibers and varicosities have been found in several other structures, including the PAG (11,25,34)., In contrast to the participation of the ventral PAG in the modulation of pain (14,46), many studies implicate the dorsal PAG in the control of defensive behavior and aversion (13). Thus, electrical stimulation of the dorsal PAG induces flight
Requests for reprints should be addressed to I. R. Pelfi, Laborat6rio de Farmacologia, Faculdade de Ci~ncias Farmac~uticas, Ribeir~o Preto, USP, Campus Universifftrio,14049 Ribeirao Preto, Sao Paulo, Brasil. 405
406
B U R D I N , G R A E F F A N D PELA
to Corraa and Graeff (6). The cannulas was fixed to the skull with two steel screws and dental cement and kept patent with a sterile obturator. After receiving a penicillin combination, IM, the animals were housed individually and allowed to recover for at least 1 week before the experiments.
,Jr
o3 12,
Procedures
