Antiallodynic Effects Of Morphine Research Articles

PACAP-PAC1 receptor inhibition is effective in opioid induced hyperalgesia and medication overuse headache models

Opioids prescribed for pain and migraine can produce opioid-induced hyperalgesia (OIH) or medication overuse headache (MOH). We previously demonstrated that pituitary adenylate cyclase activating polypeptide (PACAP) is upregulated in OIH and chronic migraine models. Here we determined if PACAP acts as a bridge between opioids and pain chronification. We tested PACAP-PAC1 receptor inhibition in novel models of opioid-exacerbated trigeminovascular pain. The PAC1 antagonist, M65, reversed chronic allodynia in a model which combines morphine with the migraine trigger, nitroglycerin. Chronic opioids also exacerbated cortical spreading depression, a correlate of migraine aura; and M65 inhibited this augmentation. In situ hybridization showed MOR and PACAP co-expression in trigeminal ganglia, and near complete overlap between MOR and PAC1 in the trigeminal nucleus caudalis and periaqueductal gray. PACAPergic mechanisms appear to facilitate the transition to chronic headache following opioid use, and strategies targeting this system may be particularly beneficial for OIH and MOH.

Intrathecal Ultra-Low Dose Naloxone Enhances the Antihyperalgesic Effects of Morphine and Attenuates Tumor Necrosis Factor-α and Tumor Necrosis Factor-α Receptor 1 Expression in the Dorsal Horn of Rats with Partial Sciatic Nerve Transection

Glutamate homeostasis and microglia activation play an important role in the development and maintenance of neuropathic pain. We designed this investigation to examine whether ultra-low dose naloxone administered alone or in combination with morphine could alter the concentration of the excitatory amino acids (EAAs) glutamate and aspartate, as well as the expression of tumor necrosis factor-α (TNF-α) and its receptors (TNFR1 and TNFR2) in the spinal cord dorsal horn of rats with partial sciatic nerve transection (PST). Male Wistar rats underwent intrathecal catheter implantation for drug delivery and were divided in 7 groups: sham-operated + saline (sham), PST + saline (S), PST + 15 ng naloxone (n), PST + 15 µg naloxone (N), PST + 10 µg morphine (M), PST + 15 ng naloxone + 10 µg morphine (Mn), PST + 15 µg naloxone + 10 µg morphine (MN). Thermal withdrawal latency and mechanical withdrawal threshold, TNF-α and TNFR expression in the spinal cord and dorsal root ganglia, and EAAs glutamate and aspartate concentration in cerebrospinal fluid dialysates were measured. Ten days after PST, rats developed hyperalgesia (P < 0.0001) and allodynia (P < 0.0001), and increased TNF-α (P < 0.0001) and TNFR1 expression (P = 0.0009) were measured in the ipsilateral spinal cord dorsal horn. The antihyperalgesic and antiallodynic effects of morphine (10 μg) were abolished by high-dose naloxone (15 μg; P = 0.0031) but enhanced by ultra-low dose naloxone (15 ng; P = 0.0015), and this was associated with a reduction of TNF-α (P < 0.0001) and TNFR1 (P = 0.0009) expression in the spinal cord dorsal horn and EAAs concentration (glutamate: P = 0.0001; aspartate: P = 0.004) in cerebrospinal fluid dialysate. Analysis of variance (ANOVA) or Student t test with Bonferroni correction were used for statistical analysis. Ultra-low dose naloxone enhances the antihyperalgesia and antiallodynia effects of morphine in PST rats, possibly by reducing TNF-α and TNFR1 expression, and EAAs concentrations in the spinal dorsal horn. Ultra-low dose naloxone may be a useful adjuvant for increasing the analgesic effect of morphine in neuropathic pain conditions.

Modification of antiallodynic and antinociceptive effects of morphine by peripheral and central action of fluoxetine in a neuropathic mice model

We have previously reported that serotonin concentration was reduced in the brain of mice with neuropathic pain and that it may be related to reduction of morphine analgesic effects. To further prove this pharmacological action, we applied fluoxetine, a selective serotonin reuptake inhibitor, to determine whether it suppressed neuropathic pain and examined how its different administration routes would affect antinociceptive and antiallodynic effects of morphine in diabetic (DM) and sciatic nerve ligation (SL) mice, as models of neuropathic pain. Antiallodynia and antinociceptive effect of drugs were measured by using von Frey filament and tail pinch tests, respectively. Fluoxetine given alone, intracerebroventicularly (i.c.v., 15 microg/mouse) or intraperitoneally (i.p., 5 and 10 mg/kg) did not produce any effect in either model. However, fluoxetine given i.p. enhanced both antiallodynic and antinociceptive effects of morphine. Administration of fluoxetine i.c.v., slightly enhanced only the antiallodynic effect of morphine in SL mice. Ketanserine, a serotonin 2A receptor antagonist (i.p., 1 mg/kg) and naloxone, an opioid receptor antagonist (i.p., 3 mg/kg), blocked the combined antinociceptive effect of fluoxetine and morphine. Our data show that fluoxetine itself lacks antinociceptive properties in the two neuropathy models, but it enhances the analgesic effect of morphine in the periphery and suggests that co-administration of morphine with fluoxetine may have therapeutic potential in treatment of neuropathic pain.

Disability of Development of Tolerance to Morphine and U-50,488H, a Selective κ-Opioid Receptor Agonist, in Neuropathic Pain Model Mice

We examined the analgesic and anti-allodynic effects of morphine and U-50,488H (trans-(±)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl]-cyclohexyl)-benzeneacetamide methanesulfonate salt), a selective κ-opioid receptor agonist, and the development of tolerance to their effects in neuropathic pain model mice induced by sciatic nerve ligation (SNL). In the tail-pinch method, morphine at 10 mg/kg, s.c. produced a weak analgesic effect in SNL mice; however, U-50,488H at 5 mg/kg, s.c. produced an analgesic effect equipotent to that in normal mice. In contrast, morphine produced an adequate analgesic effect when given either intracerebroventricularly (i.c.v.) or intrathecally (i.t.), but U-50,488H only produced analgesia when given i.t. Repeated administration of morphine (either i.c.v. or i.t.) or U-50,488H (either s.c. or i.t.), did not induce tolerance to the effect. In the static allodynia test with an application of von Frey filaments, both compounds given s.c. suppressed the allodynic effect, but in the dynamic allodynia test involving lightly stroking the plantar surface with a cotton bud, only U-50,488H produced an anti-allodynic effect. Repeated administrations of both compounds did not develop tolerance to these anti-allodynic effects. Thus, U-50488H was found to be a highly effective at blocking hyperalgesia and allodynia in nerve injury, and these findings suggest that κ-opioid receptor agonists are attractive pharmacological targets for the control of patients with neuropathic pain.

The Mechanical Antiallodynic Effect of intrathecal Morphine and R-Phenylisopropyl-Adenosine in Rats with Spinal Nerve Ligation

Background: A nerve ligation injury may produce a pain syndrome including mechanical allodynia. Usually the antiallodynic effect of morphine is diminished in a neuropathic rat model. However, in a previous study, spinal morphine was found to have an antiallodynic effect in a neuropathic rat model. Therefore, the present study was performed to observe the mechanical antiallodynic effects of spinal morphine and R-PIA, and to investigate the relationship between the two. Methods: Male SD rats were prepared by tightly ligating the left L5 and L6 spinal nerve and by implanting a lumbar intrathecal catheter. In study 1, each of the 5 groups (morphine at 3 or 10, adenosine A1 receptor agonist (R-PIA) at 3 or 10, or saline) were administered intrathecally to examine changes in the mechanical allodynia threshold. In study 2, selective adenosine A1 receptor antagonist (DPCPX 10) was administered to investigate the reversal of the mechanical antiallodynic effect in the 4 treated groups. In study 3, we observed the pretreatment effect of DPCPX 10. The mechanical allodynic thresholds for left hindpaw withdrawal to von Frey hairs were assessed and converted to %MPE. Results: In study 1, the mechanical allodynic threshold was significantly increased in a similar pattern by intrathecal morphine (3, 10) and R-PIA (3, 10) (P ＜ 0.05). In study 2, the allodynic threshold of morphine was insignificantly decreased by intrathecal DPCPX pretreatment. The mechanical allodynic threshold of R-PIA 3 was decreased by intrathecal DPCPX (P ＜ 0.05). In study 3, the antiallodynic effect of morphine was not influenced by DPCPX pretreatment. Conclusions: Intrathecal morphine and R-PIA produced the antiallodynic effect. The antiallodynic effect of morphine was slightly decreased by DPCPX 10. Therefore, it was suggested that the antiallodynic effect of morphine might be, at least in part, mediated by adenosine in a rat model of spinal nerve ligation.

Enhanced thermal antinociceptive potency and anti-allodynic effects of morphine following spinal administration of endotoxin

Recently, an animal model of central inflammation characterized by widespread cutaneous hyperalgesia and allodynia following intracerebroventricular (i.c.v.) administration of lipopolysaccharide (LPS) was described. In the present study, we demonstrate that central administration of LPS via intrathecal (i.t.) injection produces bilateral tactile allodynia and thermal hyperalgesia in the rat. Also, the effects of morphine-induced antinociception were determined in this model. Here we demonstrate enhanced thermal antinociceptive potency of i.t. morphine in LPS-treated rats compared to controls. Intrathecal morphine was also effective in alleviating the tactile allodynia induced by LPS. Both the antinociceptive and anti-allodynic effects produced by i.t. morphine were completely antagonized by pretreatment with subcutaneous naloxone (1 mg kg −1). This study demonstrates the presence of both heat hyperalgesia and mechanical allodynia following central administration of LPS, and an increased antinociceptive potency of i.t. morphine in this model.

The effect of combined systemic administration of morphine and L‐NAME, a nitric oxide synthase inhibitor, on behavioral signs of neuropathic pain in rats

AbstractThe controversy over using opiods for managing chronic neuropathic pain is widely acknowledged, and nitric oxide (NO) is suggested to play an important role in the maintenance of the behavioral signs of neuropathic pain. We evaluated the effect of combined systemic administration of morphine and NG‐nitro‐L‐arginine‐methyl ester (L‐NAME), a NO synthase (NOS) inhibitor, on allodynia in the spinal nerve ligation model of pain in rats. Nerve injury was produced by tight ligation of the left L5 and L6 spinal nerves and this procedure resulted in neuropathic pain behaviors in the ipsilateral hindlimb. Mechanical and cold allodynia were detected, respectively, by application of von Frey filaments or acetone to the plantar surface of the foot. Morphine (0.1–10 mg/kg, i.p.) and L‐NAME (3–30 mg/kg, i.p.) reduced mechanical and cold allodynia with their higher doses. Combining subthreshold dose of L‐NAME (3 mg/kg, i.p.) with morphine, an appreciable increase in the antiallodynic effect of morphine was observed. This effect was prevented by L‐arginine (500 mg/kg, i.p.) and naloxone (1 mg/kg, i.p.). These results suggest that combining morphine with a NOS inhibitor may be a promising approach in the treatment of neuropathic pain.

The Interaction of Morphine and Adenosine Receptor Agonists on Antiallodynia in Rats with a Nerve Ligation Injury

Background: A Nerve ligation injury may produce a pain syndrome that includes tactile allodynia. Reversal effects on tactile allodynia have been demonstrated after an intrathecal administration of adenosine analogues or morphine. Adenosine receptor agonists have been known to have antinociceptive and antiallodynic effects in many animal and human studies. We examined the drug interactions between morphine and adenosine agonists in a rat model of a nerve ligation injury. Methods: Male Sprague Dawley rats were prepared with a tight ligation of the left lumbar 5 th and 6 th spinal nerves and chronic lumbar intrathecal catheter implantation for drug administration. We measured the tactile allodynia by applying von Frey filaments ipsilateral to the lesioned hindpaw. Thresholds for paw withdrawal were assessed. Morphine (1-30g), adenosine (1-30g) and R-PIA (0.1-10g) were administered to obtain the dose-response curves and the 50% effective dose (ED50). Fractions of ED50 values were administered to establish the ED50 of drug combinations. Drug interactions were evaluated by the fractional and isobolographic analyses. Allodynic thresholds for left lesioned hindpaw withdrawal to the von Frey hairs test were assessed and converted to % maximal possible effect (%MPE). Results: The antiallodynic effect of morphine, adenosine, and R-PIA were produced in a dose dependent manner. The antiallodynic effects of combinations showed a similar pattern. Isobolographic analysis revealed a synergistic interaction for the morphine-R-PIA combination but not for the morphine-adenosine combination. However, fractional analysis produced a synergistic result for two combination groups. Conclusions: The results demonstrated that intrathecal co-administration of adenosine A1 receptors agonist and morphine showed the synergistic effect on nerve ligation injury induced allodynia.

Dextromethorphan potentiates the effect of morphine in rats with peripheral neuropathy.

Neuropathic pain responds poorly to opioids. We now report that combination of systemic morphine (2 mg/kg) and dextromethorphan (45 mg/kg), a clinically available antitussive with NMDA-antagonist properties, markedly alleviated mechanical and cold allodynia-like behavior in a rat model of peripheral mononeuropathy. Neither drug produced a significant effect on its own at these doses. The anti-allodynic effect of morphine plus dextromethorphan was reversed by naloxone. The present results suggest that a combination of NMDA-antagonist and opiates might be effective in treating neuropathic pain. Furthermore, the effect of this drug combination is mainly mediated via opioid receptors.