Elsevier

Neuroscience

Volume 118, Issue 1, 25 April 2003, Pages 227-232
Neuroscience

Research paper
Behavioral evidence linking opioid-sensitive GABAergic neurons in the ventrolateral periaqueductal gray to morphine tolerance

https://doi.org/10.1016/S0306-4522(02)00822-9Get rights and content

Abstract

Tolerance develops to the antinociceptive effects of morphine with repeated microinjections into the ventrolateral periaqueductal gray (PAG). This tolerance could be caused by adaptations within the PAG or anywhere along the descending pathway (rostral ventromedial medulla to spinal cord). If tolerance is caused by a change along the descending pathway, then tolerance should develop to direct activation of PAG output neurons. However, if tolerance is caused by a change to neurons within the PAG, then tolerance will not occur with repeated direct activation of PAG output neurons. This hypothesis was tested by assessing antinociception following repeated microinjections of the GABA antagonist bicuculline and the excitatory amino acid kainate into the ventrolateral PAG. Microinjection of bicuculline and kainate produces antinociception by disinhibition and direct excitation of ventrolateral PAG output neurons, respectively. Repeated administration of these drugs into the ventrolateral PAG produced antinociception with no evidence of tolerance. That is, the hot-plate latency and responsiveness to intraplantar formalin administration was comparable whether rats received the drug for the first or fifth time. Moreover, microinjection of bicuculline or kainate produced comparable antinociception in rats pretreated with these drugs and saline-treated control rats.

These data demonstrate that repeated activation of ventrolateral PAG output neurons is not sufficient to produce tolerance. Thus, tolerance must be caused by a change in neurons preceding output neurons in this circuit, presumably opioid-sensitive GABAergic neurons.

Section snippets

Subjects

Male, Sprague–Dawley rats (300–500 g; Animal Technologies Inc., Fremont, CA, USA) were anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and implanted with a guide cannula (23-gauge×12 mm long) aimed at the right ventrolateral PAG (anterior+1.0 mm; lateral+0.6 mm, ventral−4.9 mm from lambda). The guide cannula was held in place with dental acrylic affixed to two screws in the skull. A 10-mm stylet was inserted into the guide, and the rat was allowed to recover for 1 week prior to testing.

Microinjections

Experiment 1: bicuculline microinjections

Forty-three rats had injection sites located in the ventrolateral PAG (Fig. 1). Of these, 22 were pretreated with bicuculline and 21 with saline. These groups were similar prior to testing with bicuculline as indicated by the effect of the morphine screening test. Table 1 shows that microinjection of morphine into the ventrolateral PAG produced an increase in hot-plate latency and a decrease in open-field activity in both groups. Both the bicuculline and saline groups were injected with

Discussion

The present data show no evidence of tolerance to the antinociceptive effect of microinjecting the GABA antagonist bicuculline or the excitatory amino acid kainate into the ventrolateral PAG. Microinjection of bicuculline and kainate produced antinociception on trial 5 that was comparable to the antinociception produced on trial 1 and that produced in saline-pretreated controls receiving these drugs for the first time. This finding is in direct contrast to the tolerance that develops with

Acknowledgements

This investigation was supported in part by funds provided for medical and biological research by the State of Washington Initiative Measure No. 171 and by National Institute on Drug Abuse grant DA12506.

References (24)

  • D. Budai et al.

    Endogenous opioid peptides acting at mu-opioid receptors in the dorsal horn contribute to midbrain modulation of spinal nociceptive neurons

    J Neurophysiol

    (1998)
  • B. Chieng et al.

    Inhibition by opioids acting on mu-receptors of GABAergic and glutamatergic postsynaptic potentials in single rat periaqueductal gray neurones in vitro

    Br J Pharmacol

    (1994)
  • Cited by (0)

    View full text