Role of adenosine in the spinal antinociceptive and morphine modulatory actions of neuropeptide FF analogs

The neuropeptide FF (Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) and its synthetic analogs bind to specific receptors in the spinal cord to produce antinocic eptive effects that are partially attenuated by opioid antagonists, and at sub-effective doses neuropeptide FF receptor agonists augment spinal opioid antinociception. Since adenosine plays an intermediary role in the product ion of spinal opioid antinociception, this study investigated whether this purine has a similar role in the expression of spinal effects produced by n europeptide FF receptor agonists. In rats bearing indwelling spinal cathete rs, injection of adenosine receptor agonists, N6-cyclohexyladenosine (CHA, 1.72 nmol) and N-ethylcarboxiamidoadenosine (NECA, 1.95 nmol), as well as m orphine (13.2 nmol) elicited antinociception in the tail-flick and paw-pres sure tests. Pretreatment with intrathecal 8-phenyltheophylline (5.9 and 11. 7 nmol), an adenosine receptor antagonist, blocked the effect of all three agents without influencing baseline responses. Administration of two synthe tic neuropeptide FF (NPFF) analogs, [D-Tyr(1),(NMe)Phe(3)]NPFF (1DMe, 0.86 nmol) and [D-Tyr(1),D-leu(2),D-Phe(3)]NPFF (3D, 8.6 nmol) produced sustaine d thermal and mechanical antinociception. Pretreatment with doses of intrat hecal 8-phenyltheophylline (5.9, 11.7 and 23.5 nmol), producing adenosine r eceptor blockade, significantly inhibited the antinociceptive effects of 1D Me or 3D. Injection of a sub-antinociceptive dose of 1DMe (0.009 nmol) sign ificantly augmented the antinociceptive effect of intrathecal morphine (13. 2 nmol) in the tail-flick and paw-pressure tests. Intrathecal 8-phenyltheop hylline (11.7 nmol) reduced the effect of this combination. Administration of low dose of 1DMe (0.009 nmol) or 3D (0.009 nmol) very markedly potentiat ed the antinociceptive actions of the adenosine receptor agonist, N6-cycloh exyladenosine (0.43, 0.86 and 1.72 nnol) in the tail-flick and paw-pressure tests 50 min after injection. The results suggest that the antinociceptive and morphine modulatory effects resulting from activation of spinal NPFF r eceptors could be due to an increase in the actions or availability of aden osine. (C) 2000 Elsevier Science B.V. All rights reserved.