A combination of gabapentin and morphine mediates enhanced inhibitory effects on dorsal horn neuronal responses in a rat model of neuropathy.
BACKGROUND
Peripheral nerve damage can result in severe, long-lasting pain accompanied by sensory deficits. This neuropathic pain remains a clinical problem, and effective morphine analgesia is often limited by intolerable side effects. The antiepileptic gabapentin has recently emerged as an alternative chronic pain treatment. Improved management of the diverse symptoms and mechanisms of neuropathic pain may arise from combination therapy, based on multiple pharmacologic targets and low drug doses.


METHODS
The authors used the Kim and Chung rodent model of neuropathy to induce mechanical and cold allodynia in the ipsilateral hind paw. In vivo electrophysiologic techniques were subsequently used to record evoked dorsal horn neuronal responses in which the effects of systemic morphine and gabapentin were investigated, both individually and in combination.


RESULTS
Morphine (1 and 4 mg/kg) inhibited neuronal responses of control rats but not after neuropathy. Gabapentin (10 and 20 mg/kg) inhibited neuronal responses in nerve injured rats and to a lesser extent in sham rats but not in naive rats. In the presence of gabapentin (ineffective low dose of 10 mg/kg), morphine (1 and 3 mg/kg) mediated significant inhibitory effects in all experimental groups, with the greatest inhibitions observed in spinal nerve-ligated and sham-operated rats. After neuropathy, inhibitions mediated by morphine were significantly increased in the presence of gabapentin compared with morphine alone.


CONCLUSIONS
After spinal nerve ligation, the inhibitory effects of systemic morphine on evoked dorsal horn neuronal responses are reduced compared with control, whereas the effectiveness of systemic gabapentin is enhanced. In combination with low-dose gabapentin, significant improvement in the effectiveness of morphine is observed, which demonstrates a clinical potential for the use of morphine and gabapentin combinational treatment for neuropathic pain.
Matthews
Elizabeth A
EA
Department of Pharmacology, University College London, London, United Kingdom. e,matthews@ucl.ac.uk
Dickenson
Anthony H
AH
D000085:Acetates / Q000494:pharmacology*; D000588:Amines; D000700:Analgesics / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D003509:Cyclohexanecarboxylic Acids; D004594:Electrophysiology; D000077206:Gabapentin; D008026:Ligation; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D020671:Posterior Horn Cells / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013118:Spinal Cord Diseases / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D013127:Spinal Nerves / Q000502:physiology; D005680:gamma-Aminobutyric Acid
D000085:Acetates; D000588:Amines; D000700:Analgesics; D000701:Analgesics, Opioid; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D009020:Morphine