Formalin-induced pain and mu-opioid receptor density in brain and spinal cord are modulated by A1 and A2a adenosine agonists in mice

Brain Res. 2002 Nov 29;956(2):339-48. doi: 10.1016/s0006-8993(02)03568-0.


The effects of adenosine analogues on pain have been shown to depend on the subtype receptor involved as well as on the nociceptive stimuli and on the route of administration. In the first experiment of the present study intraperitoneal administration of the A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) (0.015, 0.03, 0.09, 0.15, 0.21, 0.3 mg/kg) induced dose-dependent analgesia to formalin pain in both phases characterizing the test. The A(2a) receptor agonist 2-[p-2-(carbonyl-ethyl)-phenyethylamino]-5'-N-ethylcarboxaminoadenosine (CGS21680) (0.025, 0.05, 0.1, 0.15 mg/kg) significantly affected behavioral responses to formalin only during the early phase. In the second experiment the interaction between adenosine and the opioid system was investigated through both behavioral and neurochemical studies. The opioid antagonist naltrexone (0.1 mg/kg) did not affect the antinociception induced by CPA (0.21 mg/kg) and CGS21680 (0.05 mg/kg). Autoradiographic studies showed that formalin administration significantly modified mu-opioid receptor density in the superficial laminae of the spinal cord and in the paracentral thalamic nucleus, contralateral to the side of formalin injection. CPA and CGS21680 counteracted these effects induced by formalin. In conclusion the present study confirms and extends the role of A(1) and A(2a) adenosine receptors in the modulation of inflammatory pain and their interaction with the mu-opioid system, and suggests further investigation of these purinergic receptors from a therapeutic perspective.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology*
  • Animals
  • Autoradiography
  • Central Nervous System / drug effects*
  • Central Nervous System / metabolism
  • Fixatives
  • Formaldehyde
  • Male
  • Mice
  • Motor Activity / drug effects
  • Naltrexone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Pain / chemically induced
  • Pain / drug therapy*
  • Pain / metabolism
  • Periaqueductal Gray / drug effects
  • Phenethylamines / pharmacology*
  • Purinergic P1 Receptor Agonists
  • Receptor, Adenosine A2A
  • Receptors, Opioid, mu / drug effects*
  • Receptors, Opioid, mu / metabolism
  • Receptors, Purinergic P1 / metabolism*
  • Spinal Cord / drug effects
  • Thalamus / drug effects


  • Fixatives
  • Narcotic Antagonists
  • Phenethylamines
  • Purinergic P1 Receptor Agonists
  • Receptor, Adenosine A2A
  • Receptors, Opioid, mu
  • Receptors, Purinergic P1
  • 2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine
  • Formaldehyde
  • N(6)-cyclopentyladenosine
  • Naltrexone
  • Adenosine