Morphine In Naive Rats Research Articles

Gabapentin attenuates morphine tolerance through interleukin-10

In this study, we examined the anti-inflammatory mechanism by which gabapentin attenuates morphine tolerance in rats. Gabapentin enhanced the antinociceptive effect of morphine and attenuated chronic morphine tolerance when administered intrathecally with morphine in naive rats. We found that a 7-day chronic intrathecal injection of morphine increased the expression of proinflammatory cytokines and decreased interleukin-10 (IL-10) levels in the rat spinal cord. These changes were minimized when gabapentin was combined with morphine. In addition, the effects of gabapentin were reversed by coadministration of the anti-IL-10 antibody. Our findings indicate that enhancement of the antinociceptive effect of morphine by gabapentin may occur through upregulation of the anti-inflammatory cytokine IL-10 and inhibition of proinflammatory cytokines in the rat spinal cord.

No Effect of Morphine on Ventral Tegmental Dopamine Neurons during Withdrawal

Substantial evidence indicates that the ventral tegmental area (VTA) of the mesocorticolimbic dopaminergic (DA) system has a key role in mechanisms of opiate dependence. Although DA neurons have been studied extensively, little is known about their activity and their response to acute morphine during morphine dependence. We recorded the activity of VTA DA neurons in five groups of anesthetized rats: drug-naive (naive) rats, morphine-dependent [(MD) implanted with pellets] rats, and three groups of withdrawn rats. Withdrawals either were precipitated by naltrexone or occurred spontaneously 24 h or 15 d after pellet removal. We confirmed that acute morphine in naive rats produced a marked increase in the firing of VTA DA neurons. We also found that the basal firing rate of VTA DA neurons was markedly higher in MD than in naive rats; however, in MD rats, acute morphine failed to increase DA activity. We confirmed inhibition of VTA DA activity in MD rats in response to precipitated withdrawal; however, this inhibition resulted only in a normalization of the firing rate to that of naive animals. In rats that had spontaneous withdrawal after 24 h or 15 d, the activity of VTA DA neurons was similar to that of naive rats, and an acute injection of morphine failed to alter their activity. Our results indicate that VTA DA neurons show long-lasting tolerance to the acute effect of morphine after withdrawal. These findings show that VTA DA neural activity is unlikely to be a factor in the altered behavioral responses that occur with acute morphine or naltrexone administration after chronic opiate exposure.

Spinal PKC activity and expression: role in tolerance produced by continuous spinal morphine infusion

It has been hypothesized that spinal morphine tolerance results from protein kinase C (PKC) mediated phosphorylation. Chronic lumbar intrathecal (i.t.) infusion of morphine (20 nmol/μl/h) was shown to produce antinociception on day 1 (d1) that disappeared by d5 (tolerance). On d6, a bolus i.t. probe dose of morphine (60 nmol) produced a more profound antinociception in saline-infused rats than in morphine-infused rats. Coinfusion of morphine with a PKC inhibitor, chelerythrine, prevented tolerance to the probe morphine dose. Bolus i.t. chelerythrine or GF109203X (GF), another PKC inhibitor, on d5, but not the inactive homologue of GF Bisindolymaleimide V, also blocked development of tolerance after 24 h. I.t. morphine infusion, but not saline, produced a 2-fold increase in dorsal horn PKC phosphorylating activity and in the expression of PKC α/ γ. Bolus chelerythrine on d5 after spinal morphine infusion blocked upon an increase in PKC activity, confirming that at the behaviorally active dose the drug had the intended biochemical effect upon spinal PKC activity. PKC activity and protein expression did not change when assessed 1 h after bolus i.t. morphine in naive rats. Thus, tolerance produced by morphine infusion is dependent upon an increase in local phosphorylating activity by PKC. Blocking the PKC activity prevents expression of the morphine tolerance.

The tegmental pedunculopontine nucleus: a brain-stem output of the limbic system critical for the conditioned place preferences produced by morphine and amphetamine

The potent reinforcing properties of psychoactive drugs have been attributed to the activation of motivational processes localized to the limbic system. We investigated the role of 2 specific outputs of the forebrain limbic system, the tegmental pedunculopontine nucleus (TPP) and the periacqueductal gray (PAG) of the pons-midbrain, in the positive motivational effects of morphine and amphetamine. We now report that the TPP, but not the PAG nor other nearby regions, is a critical site in the neural system subserving the rewarding effects of both opiates and stimulants. Bilateral ibotenic acid lesions of the TPP blocked the positive reinforcing effects of both morphine and amphetamine in naive rats as measured in a conditioned place preference paradigm. However, TPP lesioned animals were still capable of acquiring a conditioned place preference to an environment paired with the peripheral opiate antagonist methylnaltrexone. This suggested that TPP lesions did not cause nonspecific deficits in the basic learning mechanisms underlying conditioned place preferences. Furthermore, while the TPP was critical for the acquisition of a conditioned preference to an environment paired with morphine in naive rats, rats that had acquired a morphine conditioned place preference prior to the lesions were capable of retaining and demonstrating these place preferences after lesions of the TPP. This again demonstrates that TPP lesions are producing an unconditioned deficit in motivation rather than a deficit in learning or memory. Finally, direct comparisons of the place preference data of individual animals with their correspondent TPP lesion sites indicated that the most effective lesions overlapped to a greater degree TPP perikarya with descending, rather than ascending, axons. This suggests that motivational information generated by drug stimuli acting at "upstream" neural structures flows in a descending direction through the TPP region of the brain stem. These results suggest that opiates and stimulants must ultimately activate a single brain-stem substrate in order to have a positive motivational impact. It is hypothesized that the neural circuits mediating the rewarding effects of drug stimuli acting at forebrain sites exit the limbic system in the TPP region of the brain stem, where motivation may ultimately influence or be isomorphic with the elicitation of motor responses subserving approach and exploration.

Reversal of tolerance to morphine but no potentiation of morphine-induced analgesia by antiserum against cholecystokinin octapeptide

Tolerance to morphine analgesia was induced in rats by chronic treatment with morphine (5–30 mg kg , t.i.d. for 6 days). Intracerebroventricular (i.c.v.) injection of antiserum against cholecystokinin octapeptide (CCK-8) reversed tolerance to morphine by 50% ( P < 0.001). Intrathecal (ith) injection of the CCK-8 antiserum produced a similar, although less marked, reversal of tolerance to morphine. Rats made tolerant to analgesia induced by morphine developed a cross tolerance to electroacupuncture-induced analgesia. This cross tolerance was also reversed by the CCK-8 antiserum by more than 50% ( P < 0.001). Intracerebroventricular or intrathecal injection of the CCK-8 antiserum per se produced no significant changes in the basal level of the latency of the tail flick response, nor did it affect the analgesia induced by morphine in naive rats. The results suggest that prolonged activation of opioid receptors may trigger the CCK-8 system in the central nervous system to exert a negative feedback control, which may constitute one of the mechanisms for the development of tolerance to opioids.