Jianren Mao

Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions.

&NA; Over the last several years, compelling evidence has accumulated indicating that central hyperactive states resulting from neuronal plastic changes within the spinal cord play a critical role in hyperalgesia associated with nerve injury and inflammation. Such neuronal plastic changes may involve activation of central nervous system excitatory amino acid (EAA) receptors, subsequent intracellular cascades including protein kinase C translocation and activation as well as nitric oxide production, leading to the functional modulation of receptor‐ion channel complexes. Similar EAA receptor‐mediated cellular and intracellular mechanisms have now been implicated in the development of tolerance to the analgesic effects of morphine, and a site of action involved in both hyperalgesia and morphine tolerance is likely to be in the superficial laminae of the spinal cord dorsal horn. These observations suggest that hyperalgesia and morphine tolerance, two seemingly unrelated phenomena, may be interrelated by common neural substrates that interact at the level of EAA receptor activation and related intracellular events. This view is supported by recent observations showing that thermal hyperalgesia develops when animals are made tolerant to morphine antinociception and that both hyperalgesia and reduction of the antinociceptive effects of morphine occur as a consequence of peripheral nerve injury. The demonstration of interrelationships between neural mechanisms underlying hyperalgesia and morphine tolerance may lead to a better understanding of the neurobiology of these two phenomena in particular and pain in general. This knowledge may also provide a scientific basis for improved pain management with opiate analgesics.

THE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONIST DEXTROMETHORPHAN SELECTIVELY REDUCES TEMPORAL SUMMATION OF SECOND PAIN IN MAN

&NA; Oral doses of dextromethorphan (DM), a common cough suppressant and Symbol (NMDA) receptor antagonist, and their vehicle control were given on a double‐blind basis to normal volunteer human subjects who rated intensities of first and second pain in response to repeated painful electric shocks and repeated 52°C heat pulses. Doses of 30 and 45 mg, but not 15 mg, were effective in attenuating temporal summation of second pain, a psychophysical correlate of temporal summation of C afferent‐mediated responses of dorsal horn nociceptive neurons, termed ‘wind‐up’. By contrast, neither first nor second pain evoked by the first stimulus in a train of stimuli were affected by any of these doses of DM. These results further confirm temporal summation of second pain as a psychophysical correlate of wind‐up by providing evidence that DM selectively reduces temporal summation of second pain, as has been shown for wind‐up. Symbol. No caption available

Experimental mononeuropathy reduces the antinociceptive effects of morphine: implications for common intracellular mechanisms involved in morphine tolerance and neuropathic pain

&NA; Recent evidence suggests that hyperalgesia and morphine tolerance, two seemingly unrelated phenomena, have in common certain neural substrates such as activation of the N‐methyl‐D‐aspartate (NMDA) receptor and the subsequent intracellular activation of protein kinase C and nitric oxide. Should common cellular elements be involved in hyperalgesia and morphine tolerance, these cellular and intracellular commonalities might be expected to result in interactions between these two phenomena. Indeed, our previous studies have shown that thermal hyperalgesia develops when animals are made tolerant to the antinociceptive effects of morphine. In this study, we examined the hypothesis that reduction of morphine antinociception occurs following unilateral ligation of the ratss sciatic nerve, a procedure which produces symptoms of a neuropathic pain syndrome including thermal hyperalgesia. When tested using the paw‐withdrawal test on day 8 (D8) after either nerve ligation or sham operation, a single intrathecal treatment with 10 &mgr;g morphine sulfate (30 min after administration) produced significant antinociception in sham‐operated rats but not in nerve‐injured ones. These results also were obtained when thermal hyperalgesia was reversed in nerve‐injured rats by the non‐competitive NMDA receptor antagonist MK‐801. Consistently, 8 days after sciatic nerve ligation but not after a sham operation, an approximately 6‐fold rightward shift occurred in the morphine antinociceptive dose‐response curve. This rightward shift of the morphine antinociceptive dose‐response curve did not occur at 24 h after either nerve ligation or sham operation. In addition, once daily treatment with 10 nmol MK‐801 from D2 to D7 after nerve ligation prevented both the development of thermal hyperalgesia and the rightward shift of the morphine antinociceptive dose‐response curve on D8. The results indicate that the antinociceptive effects of morphine are reduced in nerve‐injured rats in the absence of daily exposure to morphine and that the NMDA receptor activation may have a critical role in mechanisms of this phenomenon. These data provide further evidence indicating that interactions do occur between neural mechanisms underlying thermal hyperalgesia and morphine tolerance.

Intrathecal MK-801 and local nerve anesthesia synergistically reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy

The hyperalgesia and spontaneous pain that occur following peripheral nerve injury may be related to abnormal peripheral input or altered central activity, or both. The present experiments investigated these possibilities by examining the effects of MK-801 (a non-competitive N-methyl-D-aspartate, NMDA, receptor antagonist) and bupivacaine (a local anesthetic agent) on thermal hyperalgesia and spontaneous nociceptive behaviors in rats with painful peripheral mononeuropathy. Peripheral mononeuropathy was produced by loosely ligating the rats common sciatic nerve, a procedure which causes chronic constrictive injury (CCI) of the ligated nerve. The resulting hyperalgesia to radiant heat and spontaneous nociceptive behaviors was assessed by using a foot-withdrawal test and a spontaneous pain behavior rating method, respectively. CCI rats receiving 4 daily intraperitoneal (i.p.) MK-801 injections (0.03, 0.1, 0.3 mg/kg) beginning 15 min prior to nerve ligation exhibited less hyperalgesia (i.e., longer foot-withdrawal latencies) on days 3, 5, 7, 10, and 15 after nerve ligation as compared to those receiving saline injections. Thermal hyperalgesia also was reduced when a single MK-801 injection was given intrathecally (i.t.) onto the spinal cord lumbar segments on Day 3 after nerve ligation. This effect of postinjury MK-801 treatment was dose-dependent (2.5-20 nmol) and lasted for at least 48 h after injection. Moreover, i.t. injection of MK-801 (10 nmol) reliably lowered spontaneous pain behavior rating scores in CCI rats compared to those in the saline group. The spinal site of MK-801 action is situated within the caudal (probably lumbar) spinal cord, since i.t. injection of MK-801 (10 nmol) onto the spinal cord thoracic segments did not affect thermal hyperalgesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Intrathecal treatment with dextrorphan or ketamine potently reduces pain-related behaviors in a rat model of peripheral mononeuropathy

The therapeutic effects of dextrorphan and ketamine, two non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists, on neuropathic pain-related behaviors were examined in rats with peripheral mononeuropathy induced by loose ligation of the common sciatic nerve (chronic constrictive injury, CCI). Four daily intrathecal treatments (beginning 1 h after nerve ligation) with dextrorphan or ketamine (12.5-100 nmol) reliably attenuated hyperalgesia to radiant heat and spontaneous pain-related behaviors in CCI rats. Thermal hyperalgesia also was reduced in CCI rats receiving a single intrathecal treatment with either dextrorphan or ketamine (50 and 100 nmol for each compound) on day 3 after nerve ligation when thermal hyperalgesia was well developed. Since both dextrorphan and ketamine are currently utilized in other clinical applications, the results suggest a new therapeutic utility of these old compounds in treatment of neuropathic pain syndromes resulting from peripheral nerve injury.

Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy

Central activation of excitatory amino acid receptors has been implicated in neuropathic pain following nerve injury. In a rat model of painful peripheral mononeuropathy, we compared the effects of non-competitive NMDA receptor antagonists (MK 801 and HA966) and a non-NMDA receptor antagonist (CNQX) on induction and maintenance of thermal hyperalgesia induced by chronic constrictive injury (CCI) of the rat common sciatic nerve. Thermal hyperalgesia to radiant heat was assessed by using a foot-withdrawal test and NMDA/non-NMDA receptor antagonists were administered intrathecally onto the lumbar spinal cord before and after nerve injury. Four daily single treatments with 20 nmol HA966 or CNQX beginning 15 min prior to nerve ligation (pre-injury treatment), reliably reduced thermal hyperalgesia in CCI rats on days 3, 5, 7 and 10 after nerve ligation. Thermal hyperalgesia was also reduced in CCI rats receiving a single post-injury treatment with HA966 (20 or 80 nmol) or MK 801 (5 or 20 nmol) on day 3 after nerve ligation when thermal hyperalgesia was well developed. In contrast, a single post-injury CNQX (20 or 80 nmol) treatment failed to reduce thermal hyperalgesia or to potentiate effects of HA966 or MK 801 (5 or 20 nmol) on thermal hyperalgesia in CCI rats. Moreover, multiple post-injury CNQX treatments utilizing the same dose regime as employed for the pre-injury treatment attenuated thermal hyperalgesia but only when the treatment began 1 or 24 h (but not 72 h) after nerve ligation.(ABSTRACT TRUNCATED AT 250 WORDS)

The development of morphine tolerance and dependence is associated with translocation of protein kinase C

&NA; The development of tolerance to the analgesic effects of morphine as well as morphine dependence were greatly reduced by co‐administration with morphine of GM1 ganglioside, a substance reported to block the translocation of protein kinase C (PKC) from cytosol to membrane of neurons. Rats made tolerant to intrathecal administration of morphine showed increased membrane‐bound PKC in the superficial layers (laminae I and II) of the spinal cord dorsal horn but not in deeper layers. This increase was prevented by co‐administration with morphine of GM1 ganglioside. These results indicate that the translocation and activation of PKC may be a critical step in the development of opiate tolerance and dependence. Modulation of PKC translocation and activation may prove useful for the management of pain and opiate addiction.

Pain-related increases in spinal cord membrane-bound protein kinase C following peripheral nerve injury

Neuropathic pain following nerve injury is thought to involve central nervous system Ca(2+)-mediated neuronal plastic changes. This study provides evidence that induction and/or maintenance of post-injury neuropathic pain behaviors in the rat is associated with increases in membrane-bound protein kinase C (PKC), a Ca(2+)-dependent process known to mediate central nervous system neuronal plasticity. In addition, spinal cord administration of GM1 ganglioside, an intracellular inhibitor of PKC translocation/activation, reverses both increased levels of membrane-bound PKC and pain-related behaviors. Thus, persistent post-injury neuropathic pain may be mediated by the initiation of excitatory neuropathological processes resulting from an increase in membrane-bound PKC.

Oral administration of dextromethorphan prevents the development of morphine tolerance and dependence in rats

&NA; Combined oral administration of morphine sulfate (MS) and the over‐the‐counter antitussive drug and N‐methyl‐D‐aspartate receptor antagonist dextromethorphan (DM) prevented the development of tolerance to the antinociceptive effects of MS (15, 24, or 32 mg/kg) in rats. This combined oral treatment regimen also attenuated signs of naloxone‐precipitated physical dependence on morphine in the same rats. A wide range of ratios of MS to DM (2:1, 1:1, and 1:2) were effective for preventing the development of morphine tolerance and dependence. In addition, we provide evidence that under certain circumstances DM increases the acute antinociceptive effects of MS. All of these results indicate that oral treatment that combines DM with opiate analgesics may be a powerful approach for simultaneously preventing opiate tolerance and dependence and enhancing analgesia in humans.

Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance.

&NA; N‐Methyl‐ d‐aspartate (NMDA) receptor antagonists have been repeatedly shown to attenuate the development of opiate tolerance and dependence in rodents. In the present experiments, continuous subcutaneous infusion of either MK‐801 (0.01 mg/kg/h but not 0.005 mg/kg/h) or DM (0.133, 0.67 and 1.33 mg/kg/h) reliably prolonged the antinociceptive effect of continuous subcutaneous infusion of morphine sulfate (2.0 mg/kg/h), indicating attenuation of the development of morphine tolerance. Furthermore, this prolonged antinociception was completely reversible by naloxone (10 mg/kg, i.p.). Doses of MK‐801 and DM that were equipotent in attenuating morphine tolerance (0.01 mg/kg/h and 1.33 mg/kg/h, respectively) revealed different profiles of effects, however, on locomotor activity and naloxone‐precipitated abstinence/withdrawal symptoms. With regard to locomotor activity, rats having received continuous (48 h) subcutaneous infusion of morphine sulfate and MK‐801, but not rats having received morphine sulfate and DM, displayed a reliable and striking increase in locomotor activity as compared with rats having received morphine alone. With regard to naloxone‐precipitated withdrawal symptoms, continuous (48 h) subcutaneous co‐infusion of either MK‐801 (0.01 mg/kg/h) or DM (1.33 mg/kg/h) with morphine attenuated naloxone‐precipitated hyperalgesia as compared with rats infused with morphine alone. MK‐801 (0.01 mg/kg/h) was more effective than DM (0.133, 0.67, or 1.33 mg/kg/h), however, in reducing other naloxone‐precipitated withdrawal symptoms (teeth chattering, jumping and wet dog shakes). The effects of MK‐801 on all withdrawal symptoms were confounded, however, by the appearance of flaccidity following naloxone administration to rats having received MK‐801 and morphine. These results extend previous observations by showing that the prolonged antinociception observed following co‐administration of morphine and an NMDA antagonist is completely naloxone‐reversible, supporting the notion that this antinociception reflects prolongation of an opioid receptor‐mediated effect. The different profiles of side effects associated with MK‐801 and DM, however, suggest that (1) attenuation of naloxone‐precipitated withdrawal symptoms by MK‐801 may be an artifact of toxicity, and (2) DM may prove clinically useful for the prevention of morphine tolerance, given its lack of observable side effects when administered concurrently with morphine to rodents.